Bibliographies thématiques / HIV-1 proteasi

Littérature scientifique sur le sujet « HIV-1 proteasi »

Auteur : Grafiati
Publié le 11 mars 2023

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Articles de revues sur le sujet "HIV-1 proteasi"

1

Pan, Bowen, Sumei Li, Junwei Xiao, Xin Yang, Shouxia Xie, Ying Zhou, Jian Yang et Ying Wei. « Dual Inhibition of HIV-1 and Cathepsin L Proteases by Sarcandra glabra ». Molecules 27, no 17 (29 août 2022) : 5552. http://dx.doi.org/10.3390/molecules27175552.

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The COVID-19 pandemic continues to impose a huge threat on human health due to rapid viral mutations. Thus, it is imperative to develop more potent antivirals with both prophylactic and treatment functions. In this study, we screened for potential antiviral compounds from Sarcandra glabra (SG) against Cathepsin L and HIV-1 proteases. A FRET assay was applied to investigate the inhibitory effects and UPLC-HRMS was employed to identify and quantify the bioactive components. Furthermore, molecular docking was carried out to get a glimpse of the binding of active compounds to the proteases. Our results showed that the SG extracts (SGW, SG30, SG60, and SG85) inhibited HIV-1 protease with an IC50 of 0.003~0.07 mg/mL and Cathepsin L protease with an IC50 of 0.11~0.26 mg/mL. Fourteen compounds were identified along with eight quantified from the SG extracts. Chlorogenic acid, which presented in high content in the extracts (12.7~15.76 µg/mg), possessed the most potent inhibitory activity against HIV-1 protease (IC50 = 0.026 mg/mL) and Cathepsin L protease (inhibition: 40.8% at 0.01 mg/mL). Thus, SG extracts and the active ingredients could potentially be used to prevent/treat viral infections, including SARS-CoV-2, due to their dual-inhibition functions against viral proteases.
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Park, Jung-Ho, Yoshihiro Yamaguchi et Masayori Inouye. « Intramolecular Regulation of the Sequence-Specific mRNA Interferase Activity of MazF Fused to a MazE Fragment with a Linker Cleavable by Specific Proteases ». Applied and Environmental Microbiology 78, no 11 (23 mars 2012) : 3794–99. http://dx.doi.org/10.1128/aem.00364-12.

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ABSTRACTThe genomes of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) consist of single-stranded RNA encoding polyproteins, which are processed to individual functional proteins by virus-encoded specific proteases. These proteases have been used as targets for drug development. Here, instead of targeting these proteases to inhibit viral infection, we utilized the protease activity to activate a toxic protein to prevent viral infection. We engineered the MazE-MazF antitoxin-toxin system ofEscherichia colito fuse a C-terminal 41-residue fragment of antitoxin MazE to the N-terminal end of toxin MazF with a linker having a specific protease cleavage site for either HIV PR (HIV-1 protease), NS3 protease (HCV protease), or factor Xa. These fusion proteins formed a stable dimer (instead of the MazF2-MazE2-MazF2heterohexamer in nature) to inactivate the ACA (sequence)-specific mRNA interferase activity of MazF. When the fusion proteins were incubated with the corresponding proteases, the MazE fragment was cleaved from the fusion proteins, releasing active MazF, which then acted as an ACA-specific mRNA interferase cleaving single-stranded MS2 phage RNA. The intramolecular regulation of MazF toxicity by proteases as demonstrated may provide a novel approach for preventive and therapeutic treatments of infection by HIV-1, HCV, and other single-stranded RNA viruses.
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Capel, Elena, Glòria Martrus, Mariona Parera, Bonaventura Clotet et Miguel Angel Martínez. « Evolution of the human immunodeficiency virus type 1 protease : effects on viral replication capacity and protease robustness ». Journal of General Virology 93, no 12 (1 décembre 2012) : 2625–34. http://dx.doi.org/10.1099/vir.0.045492-0.

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The rapid spread of human immunodeficiency virus type 1 (HIV-1) in humans has been accompanied by continuous extensive genetic diversification of the virus. The aim of this study was to investigate the impact of HIV-1 diversification on HIV-1 replication capacity (RC) and mutational robustness. Thirty-three HIV-1 protease sequences were amplified from three groups of viruses: two naïve sample groups isolated 15 years apart plus a third group of protease inhibitor-(PI) resistant samples. The amplified proteases were recombined with an HXB2 infectious clone and RC was determined in MT-4 cells. RC was also measured in these three groups after random mutagenesis in vitro using error-prone PCR. No significant RC differences were observed between recombinant viruses from either early or recent naïve isolates (P = 0.5729), even though the proteases from the recent isolates had significantly lower sequence conservation scores compared with a subtype B ancestral sequence (P<0.0001). Randomly mutated recombinant viruses from the three groups exhibited significantly lower RC values than the corresponding wild-type viruses (P<0.0001). There was no significant difference regarding viral infectivity reduction between viruses carrying randomly mutated naïve proteases from early or recent sample isolates (P = 0.8035). Interestingly, a significantly greater loss of RC was observed in the PI-resistant protease group (P = 0.0400). These results demonstrate that protease sequence diversification has not affected HIV-1 RC or protease robustness and indicate that proteases carrying PI resistance substitutions are less robust than naïve proteases.
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Martínez, Miguel-Angel, Marta Cabana, Mariona Parera, Arantxa Gutierrez, José A. Esté et Bonaventura Clotet. « A Bacteriophage Lambda-Based Genetic Screen for Characterization of the Activity and Phenotype of the Human Immunodeficiency Virus Type 1 Protease ». Antimicrobial Agents and Chemotherapy 44, no 5 (1 mai 2000) : 1132–39. http://dx.doi.org/10.1128/aac.44.5.1132-1139.2000.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) resistance to antiretroviral drugs is the main cause of patient treatment failure. Despite the problems associated with interpretation of HIV-1 resistance testing, resistance monitoring should help in the rational design of initial or rescue antiretroviral therapies. It has previously been shown that the activity of the HIV-1 protease can be monitored by using a bacteriophage lambda-based genetic assay. This genetic screening system is based on the bacteriophage lambda regulatory circuit in which the viral repressor cI is specifically cleaved to initiate the lysogenic to lytic switch. We have adapted this simple lambda-based genetic assay for the analysis of the activities and phenotypes of different HIV-1 proteases. Lambda phages that encode HIV-1 proteases either from laboratory strains (strain HXB2) or from clinical samples are inhibited in a dose-dependent manner by the HIV-1 protease inhibitors indinavir, ritonavir, saquinavir, and nelfinavir. Distinct susceptibilities to different drugs were also detected among phages that encode HIV-1 proteases carrying different resistance mutations, further demonstrating the specificity of this assay. Differences in proteolytic processing activity can also be directly monitored with this genetic screen system since two phage populations compete in culture with each other until one phage outgrows the other. In summary, we present here a simple, safe, and rapid genetic screening system that may be used to predict the activities and phenotypes of HIV-1 proteases in the course of viral infection and antiretroviral therapy. This assay responds appropriately to well-known HIV-1 protease inhibitors and can be used to search for new protease inhibitors.
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McPHEE, Fiona, Patricia S. CALDERA, Guy W. BEMIS, Antony F. McDONAGH, Irwin D. KUNTZ et Charles S. CRAIK. « Bile pigments as HIV-1 protease inhibitors and their effects on HIV-1 viral maturation and infectivity in vitro ». Biochemical Journal 320, no 2 (1 décembre 1996) : 681–86. http://dx.doi.org/10.1042/bj3200681.

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Using recently developed molecular-shape description algorithms, we searched the Available Chemical Directory for known compounds similar in shape to the potent HIV-1 protease inhibitor Merck L-700,417; 15 compounds most similar in shape to the inhibitor were selected for testing in vitro. Four of these inhibited the protease at 100 µM or less and the most active of the four were the naturally occurring pigments biliverdin and bilirubin. Biliverdin and bilirubin inhibited recombinant HIV-1 protease in vitro at pH 7.8 with Ki values of approx. 1 µM, and also inhibited HIV-2 and simian immunodeficiency virus proteases. The related pyrrolic pigments stercobilin, urobilin, biliverdin dimethyl ester and xanthobilirubic acid showed similar inhibitory activity at low micromolar concentrations. Biliverdin, bilirubin and xanthobilirubic acid did not inhibit viral polyprotein processing in cultured cells, but they reduced viral infectivity significantly. At 100 µM, xanthobilirubic acid affected viral assembly, resulting in a 50% decrease in the generation of infectious particles. In contrast, at the same concentrations biliverdin and bilirubin exerted little or no effect on viral assembly but blocked infection of HeLaT4 cells by 50%. These results suggest that bile pigments might be a new class of potential lead compounds for developing protease inhibitors and they raise the question of whether hyperbilirubinaemia can influence the course of HIV infection.
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Raugi, Dana N., Robert A. Smith et Geoffrey S. Gottlieb. « Four Amino Acid Changes in HIV-2 Protease Confer Class-Wide Sensitivity to Protease Inhibitors ». Journal of Virology 90, no 2 (11 novembre 2015) : 1062–69. http://dx.doi.org/10.1128/jvi.01772-15.

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ABSTRACTProtease is essential for retroviral replication, and protease inhibitors (PI) are important for treating HIV infection. HIV-2 exhibits intrinsic resistance to most FDA-approved HIV-1 PI, retaining clinically useful susceptibility only to lopinavir, darunavir, and saquinavir. The mechanisms for this resistance are unclear; although HIV-1 and HIV-2 proteases share just 38 to 49% sequence identity, all critical structural features of proteases are conserved. Structural studies have implicated four amino acids in the ligand-binding pocket (positions 32, 47, 76, and 82). We constructed HIV-2ROD9molecular clones encoding the corresponding wild-type HIV-1 amino acids (I32V, V47I, M76L, and I82V) either individually or together (clone PRΔ4) and compared the phenotypic sensitivities (50% effective concentration [EC50]) of mutant and wild-type viruses to nine FDA-approved PI. Single amino acid replacements I32V, V47I, and M76L increased the susceptibility of HIV-2 to multiple PI, but no single change conferred class-wide sensitivity. In contrast, clone PRΔ4 showed PI susceptibility equivalent to or greater than that of HIV-1 for all PI. We also compared crystallographic structures of wild-type HIV-1 and HIV-2 proteases complexed with amprenavir and darunavir to models of the PRΔ4 enzyme. These models suggest that the amprenavir sensitivity of PRΔ4 is attributable to stabilizing enzyme-inhibitor interactions in the P2 and P2′ pockets of the protease dimer. Together, our results show that the combination of four amino acid changes in HIV-2 protease confer a pattern of PI susceptibility comparable to that of HIV-1, providing a structural rationale for intrinsic HIV-2 PI resistance and resolving long-standing questions regarding the determinants of differential PI susceptibility in HIV-1 and HIV-2.IMPORTANCEProteases are essential for retroviral replication, and HIV-1 and HIV-2 proteases share a great deal of structural similarity. However, only three of nine FDA-approved HIV-1 protease inhibitors (PI) are active against HIV-2. The underlying reasons for intrinsic PI resistance in HIV-2 are not known. We examined the contributions of four amino acids in the ligand-binding pocket of the enzyme that differ between HIV-1 and HIV-2 by constructing HIV-2 clones encoding the corresponding HIV-1 amino acids and testing the PI susceptibilities of the resulting viruses. We found that the HIV-2 clone containing all four changes (PRΔ4) was as susceptible as HIV-1 to all nine PI. We also modeled the PRΔ4 enzyme structure and compared it to existing crystallographic structures of HIV-1 and HIV-2 proteases complexed with amprenavir and darunavir. Our findings demonstrate that four positions in the ligand-binding cleft of protease are the primary cause of HIV-2 PI resistance.
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Álvarez, Enrique, Luis Menéndez-Arias et Luis Carrasco. « The Eukaryotic Translation Initiation Factor 4GI Is Cleaved by Different Retroviral Proteases ». Journal of Virology 77, no 23 (1 décembre 2003) : 12392–400. http://dx.doi.org/10.1128/jvi.77.23.12392-12400.2003.

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ABSTRACT The initiation factor eIF4G plays a central role in the regulation of translation. In picornaviruses, as well as in human immunodeficiency virus type 1 (HIV-1), cleavage of eIF4G by the viral protease leads to inhibition of protein synthesis directed by capped cellular mRNAs. In the present work, cleavage of both eIF4GI and eIF4GII has been analyzed by employing the proteases encoded within the genomes of several members of the family Retroviridae, e.g., Moloney murine leukemia virus (MoMLV), mouse mammary tumor virus, human T-cell leukemia virus type 1, HIV-2, and simian immunodeficiency virus. All of the retroviral proteases examined were able to cleave the initiation factor eIF4GI both in intact cells and in cell-free systems, albeit with different efficiencies. The eIF4GI hydrolysis patterns obtained with HIV-1 and HIV-2 proteases were very similar to each other but rather different from those obtained with MoMLV protease. Both eIF4GI and eIF4GII were cleaved very efficiently by the MoMLV protease. However, eIF4GII was a poor substrate for HIV proteases. Proteolytic cleavage of eIF4G led to a profound inhibition of cap-dependent translation, while protein synthesis driven by mRNAs containing internal ribosome entry site elements remained unaffected or was even stimulated in transfected cells.
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Álvarez, Enrique, Alfredo Castelló, Luis Menéndez-Arias et Luis Carrasco. « HIV protease cleaves poly(A)-binding protein ». Biochemical Journal 396, no 2 (15 mai 2006) : 219–26. http://dx.doi.org/10.1042/bj20060108.

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The PABP [poly(A)-binding protein] is able to interact with the 3′ poly(A) tail of eukaryotic mRNA, promoting its translation. Cleavage of PABP by viral proteases encoded by several picornaviruses and caliciviruses plays a role in the abrogation of cellular protein synthesis. We report that infection of MT-2 cells with HIV-1 leads to efficient proteolysis of PABP. Analysis of PABP integrity was carried out in BHK-21 (baby-hamster kidney) and COS-7 cells upon individual expression of the protease from several members of the Retroviridae family, e.g. MoMLV (Moloney murine leukaemia virus), MMTV (mouse mammary tumour virus), HTLV-I (human T-cell leukaemia virus type I), SIV (simian immunodeficiency virus), HIV-1 and HIV-2. Moreover, protease activity against PABP was tested in a HeLa-cell-free system. Only MMTV, HIV-1 and HIV-2 proteases were able to cleave PABP in the absence of other viral proteins. Purified HIV-1 and HIV-2 proteases cleave PABP1 directly at positions 237 and 477, separating the two first RNA-recognition motifs from the C-terminal domain of PABP. An additional cleavage site located at position 410 was detected for HIV-2 protease. These findings indicate that some retroviruses may share with picornaviruses and caliciviruses the capacity to proteolyse PABP.
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DAVIS, David A., Fonda M. NEWCOMB, Jackob MOSKOVITZ, Paul T. WINGFIELD, Stephen J. STAHL, Joshua KAUFMAN, Henry M. FALES, Rodney L. LEVINE et Robert YARCHOAN. « HIV-2 protease is inactivated after oxidation at the dimer interface and activity can be partly restored with methionine sulphoxide reductase ». Biochemical Journal 346, no 2 (22 février 2000) : 305–11. http://dx.doi.org/10.1042/bj3460305.

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Human immunodeficiency viruses encode a homodimeric protease that is essential for the production of infectious virus. Previous studies have shown that HIV-1 protease is susceptible to oxidative inactivation at the dimer interface at Cys-95, a process that can be reversed both chemically and enzymically. Here we demonstrate a related yet distinct mechanism of reversible inactivation of the HIV-2 protease. Exposure of the HIV-2 protease to H2O2 resulted in conversion of the two methionine residues (Met-76 and Met-95) to methionine sulphoxide as determined by amino acid analysis and mass spectrometry. This oxidation completely inactivated protease activity. However, the activity could be restored (up to 40%) after exposure of the oxidized protease to methionine sulphoxide reductase. This treatment resulted in the reduction of methionine sulphoxide 95 but not methionine sulphoxide 76 to methionine, as determined by peptide mapping/mass spectrometry. We also found that exposure of immature HIV-2 particles to H2O2 led to the inhibition of polyprotein processing in maturing virus particles comparable to that demonstrated for HIV-1 particles. Thus oxidative inactivation of the HIV protease in vitro and in maturing viral particles is not restricted to the type 1 proteases. These studies indicate that two distinct retroviral proteases are susceptible to inactivation after a very minor modification at residue 95 of the dimer interface and suggest that the dimer interface might be a viable target for the development of novel protease inhibitors.
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Sohraby, Farzin, et Hassan Aryapour. « Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation ». PLOS ONE 16, no 9 (27 septembre 2021) : e0257916. http://dx.doi.org/10.1371/journal.pone.0257916.

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Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and to discover the reasons for the lack of inhibitory activity of Indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of Indinavir reached over 40 Å. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98′ and Phe67/Phe67′ in the HTLV-1 protease could make strong π-Stacking interactions with Indinavir in the unbinding pathway, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and selective inhibitors for the HTLV-1 protease.
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Thèses sur le sujet "HIV-1 proteasi"

1

PAROLIN, DEBORA. « MESSA A PUNTO DI TEST ALTERNATIVI PER LO SCREENING DI POTENZIALI INIBITORI DELLA PROTEASI DI HIV-1 ». Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/231147.

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Current AIDS therapies are mainly based on the use of inhibitors targeting the active site of enzymes which are crucial for the HIV-1 replication cycle. However, due to the HIV-1 high mutation frequency and the small target size, escape mutants emerge in the long term which show resistance to such inhibitors. In the attempt to overcome this problem, it is therefore desirable to switch the attention to target enzymes which are crucial for HIV-1 survival. My attention was drawn in particular to the HIV-1 protease precursor maturation process as a possible pharmacological target. The currently available tests for the screening of putative inhibitors of enzyme activity are based on the use of HIV-1-infected cell cultures which make use of live virus and therefore are cumbersome and expensive. I therefore decided to try to set up alternative methods based on the inhibition of specific target functions by developing in vitro as well as in vivo assays based on both prokaryotic and eukaryotic cells, thus avoiding the use of live virus. These assays might be proposed as a first-line screening test which might subsequently be confirmed by performing the live-virus assay only on pre-selected promising candidates. In order to meet the objectives it was necessary to clone and to express the HIV-1 protease precursor, a molecule endowed with intrinsic folding and self-processing features, with the aim of studying its properties in vitro on isolated molecules, as well an in vivo, inside bacterial as well as eukaryotic cells. The first aim was the production and purification of the HIV-1 protease precursor in a prokaryotic cell. The purified protein would be used in immuno-enzyme assays for a detailed study of its folding process, thus gaining access to the possibility of checking the activity of putative folding inhibitors. The precursor was in fact purified making use of the His tag. However, the extraction procedures required to stabilize such a hydrophobic and maturation-prone molecule turned out to be too harsh and led to the loss of maturation capacity. Therefore, I decided to postpone this part of the project and to concentrate on the in vivo assay, which looked more promising in the short term. The second target was more quickly met: the aim was to develop a quick and reliable microbiological assay suitable to screen for folding inhibitors and for inhibitors of HIV-1 protease activity. The bacterial strain carrying the precursor gene can be induced to express the precursor which quickly maturates into protease, thus being toxic for the bacterial host. This growth arrest can be released by treatment with inhibitors of the folding process, which limit the amount of mature enzyme produced, and by inhibitors of the enzyme activity, thus resulting in bacterial cell survival. This test can be modified for large-scale application and has been used as the starting point for the development of a similar test making use of a human lymphoblastoid cell line expressing the protease precursor.
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Demitri, Nicola. « Studi strutturali di sistemi proteici e supramolecolari - studi sulla fosfodiesterasi umana,sulla proteasi da HIV-1 e su nuove classi di resorcinareni ». Doctoral thesis, Università degli studi di Trieste, 2010. http://hdl.handle.net/10077/3520.

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2008/2009
Durante i tre anni della Scuola di Dottorato in Scienze e Tecnologie Chimiche e Farmaceutiche, il Dott. Demitri Nicola si è dedicato ad un progetto di ricerca riguardante lo studio strutturale mediante diffrazione di raggi-X di diversi sistemi proteici e complessi supramolecolari. I progetti di studio sviluppati in questi tre anni di ricerca hanno riguardato: 1. Studi strutturali di complessi della proteasi da HIV-1 con nuovi inibitori. Questo enzima è un target d’elezione nel structure based drug design e nella terapia antiretrovirale attualmente adottata per il trattamento dell’AIDS. La messa a punto dei protocolli di espressione della proteina ricombinante in sistema E. coli e delle tecniche di purificazione cromatografiche ha garantito livelli di concentrazione e purezza della proteina, adeguati a fornire cristalli di dimensioni adatte agli esperimenti di diffrazione di raggi-X per lo studio strutturale mediante tecniche biocristallografiche dell’enzima in complesso con tre diversi inibitori: il farmaco commerciale, Saquinavir (SQV), e due nuove molecole sintetiche (FT99 ed EPX). Dati strutturali ad alta risoluzione di una nuova forma cristallina del complesso PR/SQV sono stati ottenuti ed hanno mostrato la presenza di disordine dell’inibitore nel sito catalitico, permettendo di discutere del fenomeno, anche in relazione ai dati strutturali già presenti in letteratura. È stata inoltre riscontrata la carbamoilazione della prolina N-terminale della proteina causata dall’utilizzo di urea come agente caotropico e ciò rappresenta la prima evidenza strutturale di tale fenomeno. Sono stati anche studiati due nuovi inibitori sviluppati nel laboratorio della Prof. Funicello (Università Degli Studi della Basilicata) e nel laboratorio del Prof. Benedetti (Università Degli Studi di Trieste): FT99 è un inibitore reversibile basato su uno scaffold sulfonammidico, mentre EPX è un isostere Phe-Phe, basato su una funzionalità epossidica e quindi disegnato per legare covalentemente la proteina ed agire come inibitore irreversibile. Cocristallizzando la proteasi con FT99 si è riscontrata l’assenza dell’inibitore nel sito catalitico (nei cristalli analizzati) e ciò può essere correlato alla relativa bassa affinità di questo inibitore per l’enzima. I dati strutturali sono stati comunque utili per indagare sulla struttura della apoproteina e per suggerire delle modifiche che portino a migliorie delle proprietà inibitorie di questo lead compound. Le mappe di densità elettronica, ottenute dai dati diffrazione del complesso PR/EPX, cristallizzato a pH 6, hanno mostrato il sito catalitico occupato in modo ordinato dall’inibitore che possedeva l’anello epossidico intatto. Questo risultato è particolarmente interessante vista l’elevata reattività che il gruppo funzionale epossidico normalmente manifesta. Per verificare questa reattività si è provato ad innescare la reazione di apertura dell’anello direttamente nel cristallo del complesso PR/EPX aumentando a 9 il pH mediante diffusione di ammoniaca. L’alterazione del pH non ha mostrato un danneggiamento dei cristalli ed il modello strutturale ottenuto dai dati di diffrazione raccolti ha mostrato che l’inibitore reagisce aprendo l’anello epossidico in modo stereospecifico per addizione di ammoniaca. 2. Espressione e purificazione della fosfodiesterasi umana PDE4B2, volta alla caratterizzazione strutturale di complessi di questo enzima con nuovi inibitori. Quest’attività di ricerca è stata condotta in collaborazione con la Chiesi Farmaceutici e con il laboratorio diretto dal Dott. Gianluca Tell dell’Università degli Studi di Udine. Le PDE hanno un ruolo fondamentale nelle patologie infiammatorie (come asma, psoriasi e dermatite allergica), e lo sviluppo di farmaci specifici in grado di regolare selettivamente l’attività di questi enzimi è particolarmente rilevante per lo sviluppo di nuovi farmaci antinfiammatori. All’inizio è stata svolta una ricerca bibliografica per conoscere le strutture e le sequenze primarie delle proteine PDE4 già cristallizzate, presenti in letteratura. Ciò ha permesso di evidenziare la sequenza del dominio catalitico della variante PDE4B2 adatta alla cristallizzazione. Scelta la sequenza da esprimere, nel laboratorio del Dott. Gianluca Tell è stato prodotto il plasmide contenente il gene della proteina scelta. Inizialmente si è deciso di provare ad usare il vettore di espressione pGEX-2T, col quale ci si è concentrati sulla purificazione della proteina di fusione GST-PDE4B2. Avendo riscontrato diverse problematiche nella purificazione di questo costrutto, si è deciso di passare all’espressione e purificazione del dominio catalitico della proteina PDE4B2 fusa con l’(His)6Tag. Purtroppo, dopo aver messo a punto un protocollo per la purificazione in condizioni denaturanti, non si è riusciti ad ottenere cristalli di proteina adatti agli studi tramite diffrazione di raggi X. Il progetto è rimasto perciò aperto ad ulteriori sviluppi, mirati al completamento della caratterizzazione strutturale, cercando nuovi approcci di purificazione della proteina in condizioni denaturanti e nuovi protocolli di purificazione che non prevedano l’uso di agenti caotropici. 3. Determinazione strutturale di sistemi supramolecolari di cavitandi chirali e non, funzionalizzati al bordo superiore con gruppi fosfonici e tiofosfonici. Quest’attività di ricerca è stata condotta in collaborazione con il gruppo del Prof. Dalcanale del Dipartimento di Chimica Organica e Industriale dell’Università di Parma. I sistemi supramolecolari in linea generale sono caratterizzati da specifiche interazioni host/guest. Il fatto che tali legami siano non-covalenti rappresenta uno dei punti di forza per questo tipo di recettori, in quanto alla base del riconoscimento molecolare c’è la possibilità di poter correggere il complesso host/guest attraverso la facile rottura e formazione di interazioni deboli. Questi sistemi sono utilizzabili come recettori, sensori di massa e dynamer, nuovi materiale interessanti dal punto di vista tecnologico, costituito da componenti modulari, di dimensioni nanometriche, capaci di rispondere a stimoli esterni. Durante questo dottorato sono stati analizzati due sistemi molto diversi. Il primo di questi è una specie capace di auto assemblare per dare spontaneamente origine a polimeri supramolecolari. La caratterizzazione di questo monomero resorcinarenico allo stato solido conferma la capacità che ha questo in soluzione di dare polimeri lineari (peculiarità confermata da misure NMR e SLS). La molecola ha mostrato di poter autoassemblare in catene polimeriche le quali si affiancano in modo ordinato allo stato solido. L’altra molecola analizzata (2PO1PSME) è un cavitando chirale utilizzabile come recettore o sensore di massa, per alcoli chirali. Lo studio di questa specie è passato attraverso una fase di messa a punto di un protocollo di purificazione del composto racemo, tramite cromatografia di affinità ottenuta per funzionalizzazione di una resina con l’amminoacido naturale treonina. La successiva caratterizzazione mediante diffrazione a raggi-X del cavitando chirale, seppur ottenuta in forma racemica, ha permesso di ottenere le caratteristiche strutturali di questo promettente recettore chirale.
XXII Ciclo
1981
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Chong, Sannie Siaw Foong. « Anisotropic potential HIV-1 protease inhibitors ». Thesis, University of Hull, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327289.

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Schaal, Wesley. « Computational Studies of HIV-1 Protease Inhibitors ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5213-2/.

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Harburn, James J. « Novel steroidal inhibitors of HIV-1 protease ». Thesis, Loughborough University, 1998. https://dspace.lboro.ac.uk/2134/14701.

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Martins, Nádia Helena. « Ensaios enzimáticos de proteases de HIV-1 de subtipos brasileiros ». Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-27042008-122417/.

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Mesmo com o grande número de estudos relacionados à proteases do subtipo B e de como suas mutações podem interferir na estrutura, na resistência a inibidores e na eficiência catalítica da enzima, existe ainda uma lacuna de como as mudanças polimórficas de proteases de HIV de outros subtipos de HIV-1 interferem nesses fatores. Nesse contexto insere-se esse trabalho, que utilizou proteases de HIV-1 isoladas de pacientes brasileiros HIV-1 infectados com o subtipo F, e outros dois mutantes, sendo que um do subtipo F e outro do subtipo B para ensaios frente a seis inibidores comercialmente disponíveis: amprenavir, indinavir, lopinavir, nelfinavir, ritonavir e saquinavir. Nossos resultados experimentais revelam que os seis inibidores comerciais estudados são significantemente menos ativos para o subtipo F e para as mutantes quando comparados ao subtipo B. Além disso, os valores de vitalidade dessas proteases também são considerados maiores que os obtidos para a proteína selvagem do subtipo B. O acúmulo de mutações comumente detectadas e o polimorfismo natural tornam a protease selvagem do subtipo F cataliticamente suficiente para manter a viabilidade do vírus e garantir alto grau de resistência cruzada frente a todos os inibidores estudados.
Despite years of intense research around the world, HIV continues to represent considerable therapeutical challenge. In order to gain more insights into resistance of polymorphic mutations of existing HIV subtypes toward commercially available pharmaceutics, we studied inhibition of subtypes B and F HIV proteases (PRs) [native and two mutant enzymes clinically identified in Brazilian patients] by six commercial inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir). Our results show that all these inhibitors have significantly higher Ki values for the subtype F HIV PR (Fwt) and both mutant enzymes than that for the B subtype HIV PR (Bwt). Furthermore, the biochemical fitnesses of these proteases, or their vitalities, are also considerably higher than that of Bwt. The accumulation of commonly detected resistant mutations in HIV PRs with natural polymorphisms turns Fwt sufficiently catalytically active to guarantee the virus viability and confers it a large degree of cross resistance against all studied inhibitors.
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Alterman, Mathias. « Design and synthesis of HIV-1 protease inhibitors ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.- bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4906-9/.

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Persson, Magnus. « Structural Studies of Bacteriophage PRR1 and HIV-1 protease ». Doctoral thesis, Uppsala universitet, Strukturell molekylärbiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-135159.

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Viruses are a diverse genera of organisms adapted to thrive in many different hosts from prokaryotic to eukaryotic. We present here the structure of bacteriophage PRR1 virus-like particle (VLP), belonging to Leviviridae family. Our structure reveals calcium ions in the VLP. Metal ions are rare in the VLP among the Leviviridae and the calcium ions were found to affect VLP stability. Gene expression in Leviviridae is controlled by a specific interaction between the viral coat protein that assembles to create the VLP, and the genomic RNA. This interaction has been thoroughly studied for the levivirus MS2 but other structural data are scarce. We have solved the structure of PRR1 VLP in complex with its RNA operator stem-loop. Binding of the stem-loop in PRR1 shows similarities to MS2 but also a different arrangement of the nucleotides, in the area of the loop that we could interpret, compared to MS2. The structures of PRR1 increase our knowledge about translational control in Leviviridae and add new information about particle stability within this family. The other virus we investigated is the more infamous human pathogen, the HIV. Because of the high mutation rate of HIV new drugs are needed on a continuous basis. We describe here the structure of two new protease inhibitors bound to the HIV-1 protease and compare them with two previously published inhibitors. Due to an extended P1´site the new compounds are able to exploit a new interaction to Phe53 in the protease structure.

Felaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 724

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Windsor, Ian William. « HIV-1 protease as a target for antiretroviral therapy ». Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122533.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2019
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 395-424).
Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV employs three enzymes in its lifecycle, including a protease that enables maturation of polyprotein precursors. Despite decades of progress studying the lifecycle of HIV and elaboration of therapeutics targeting nearly every aspect of the viral life cycle, a cure remains elusive. Breakthroughs in HIV research have occurred alongside foundational advances of molecular biology, biotechnology, and medicinal chemistry, highlighting the importance revisiting old questions with new approaches. The goal of this thesis is to advance our biochemical knowledge of HIV-I protease and develop novel therapeutics targeting this key viral enzyme. In Chapter 1, I introduce HIV and the role that HIV-1 protease plays in life cycle and current treatment strategies.
In Chapter 2, I describe an assay that enables the determination of sub-picomolar inhibition constants for competitive inhibitors of HIV-1 protease. This advance was made possible by a peptide substrate selected by phage display. I report in Chapter 3 the enhanced hydrogen bonding in the recognition of this peptide by HIV-1 protease as revealed by X-ray crystallography. The mechanism of aspartic proteases, including HIV-1 protease, has been the subject of numerous enzymology studies spanning over half a century. In Chapter 4, I reveal unappreciated non-covalent interactions within substrates of aspartic proteases that assist in catalysis. In addition to biochemical studies, this thesis includes chapters that account the development of novel antivirals. In Chapter 5, I describe the rational drug design of a boronic acid analog of the clinical inhibitor darunavir with improved potency.
A limitation of boronic acids is metabolic instability; in Chapter 6, I reveal an intramolecular protecting group that can confer oxidative stability to boronic acids. Finally, in Chapter 7, I describe an engineering approach to inactivate human RNase 1. The inactivation relies on installing a substrate for HIV- I protease, the cleavage of which unmasks cytotoxic activity. Together these chapters describe new ways forward and novel therapeutics targeting HIV-1 protease. My thesis also includes an Appendix, which describes the elaboration of boronic acid-based covalent pharmacological chaperones of human transthyretin.
by Ian William Windsor.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemistry
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Muller, Natalie Guida. « Identificação de epitopos da protease de HIV-1 alvos de respostas de células T CD4+ em pacientes infectados pelo HIV-1 ». Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5146/tde-05032010-170301/.

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Introdução: Uma proporção significante de pacientes infectados por HIV-1 (pacientes HIV-1+) tratados com inibidores de protease (IPs) desenvolve mutações de resistência. Estudos recentes têm mostrado que células T CD8+ de pacientes HIV- 1+ reconhecem epitopos de Pol incluindo mutações selecionadas por drogas. Nenhum epitopo CD4+ da protease foi descrito na base de dados de Los Alamos. Objetivo: Considerando que a protease de HIV-1 é alvo de terapia antiretroviral e que essa pressão pode selecionar mutações, nós investigamos se mutações selecionadas por IPs afetariam o reconhecimento de epitopos da protease de HIV-1 por células T CD4+ em pacientes tratados com IPs. Nós investigamos o reconhecimento de três regiões da protease preditas de conter epitopos de células T CD4+ bem como mutações induzidas por IPs por células T CD4+ em pacientes HIV- 1+ tratados com IPs. Materiais e Métodos: Quarenta pacientes HIV-1+ tratados com IPs foram incluídos (30 em uso de Lopinavir/ritonavir, 9 em uso de Atazanavir/Ritonavir e 1 em uso exclusivo de Atazanavir). Para cada paciente determinou-se a seqüência endógena da protease de HIV-1, genotipagem viral e tipagem HLA classe II. Utilizamos o algoritmo TEPITOPE para selecionar peptídeos promíscuos, ligadores de múltiplas moléculas HLA-DR, codificando as três regiões da protease de HIV-1 cepa HXB2 (HXB2 4-23, 45-64, e 76-95) e 32 peptídeos adicionais contidos nas mesmas regiões incorporando as mutações induzidas por IPs mais freqüentes no Brasil. Os 35 peptídeos foram sintetizados. Respostas proliferativas de células T CD4+ e CD8+ aos peptídeos foram determinadas por ensaios de proliferação com diluição do corante CFSE. Ensaios de ligação a alelos HLA classe II foram realizados para confirmar a promiscuidade desses peptídeos e avaliar a habilidade de se ligarem a moléculas HLA presentes em cada paciente. Resultados: Todos os peptídeos foram reconhecidos por pelo menos um paciente e respostas proliferativas de células T CD4+ e CD8+ a pelo menos um peptídeo da protease de HIV-1 foram encontradas em 78% e 75% dos pacientes, respectivamente. A terceira região (Protease 76 95) foi a mais freqüentemente reconhecida. Ao compararmos as respostas de células T às seqüências da protease do HIV-1 endógeno, observamos que a maioria dos pacientes não foi capaz de reconhecer peptídeos idênticos às essas seqüências, porém reconheceram peptídeos variantes diferentes das mesmas regiões. Apenas sete pacientes responderam às seqüências endógenas. Verificamos que diversos peptídeos endógenos que não foram reconhecidos apresentaram ausência de ligação a alelos HLA portados por estes pacientes, sugerindo que mutações selecionadas por pressão imune tenham levado ao escape de apresentação de antígeno e evasão de resposta de linfócitos T CD4+. Alternativamente, isso poderia ser explicado pela presença de um vírus replicante distinto presente no plasma uma vez que somente foram obtidas seqüências provirais. Conclusão: Epitopos selvagens e mutantes da protease do HIV-1 reconhecidos por células T CD4+ foram identificados. Também verificamos que a maior parte dos pacientes não reconheceu as seqüências da protease endógena enquanto que reconheceram seqüências variantes. O reconhecimento de seqüências não-endógenas poderia ser hipoteticamente conseqüência de alvo de populações HIV-1 minoritárias; protease de HERV que contém regiões de similaridade com a protease do HIV-1; ou seqüências de HIV-1 presentes apenas em parceiros virêmicos. A falha de reconhecimento de seqüências endógenas seria mais provável devido ao escape imune, do que ao nível de apresentação ou reconhecimento por células T. Isso implica em uma conseqüência patofisiológica na evasão de respostas de células T contra a protease de HIV-1 e no fato de ser tradicionalmente considerada uma proteína pouco antigênica
Introduction: A significant proportion of protease inhibitor (PI)-treated HIV-1 infected (HIV-1+) patients develop resistance mutations. Recent studies have shown that CD8+ T cells from HIV-1 patients can recognize antiretroviral drug-induced mutant Pol epitopes. No HIV-1 protease CD4 epitopes are described in the Los Alamos database. Aims: Given that the protease of HIV-1 is a target of antiretroviral therapy and this pressure may lead to the selection of mutations, we investigated whether PI-induced mutations affect the recognition of HIV-1 protease epitopes by CD4 + T cells in PI-treated patients. We investigated the recognition of three protease regions predicted to harbor CD4+ T cell epitopes as well as PI-induced mutations by CD4+ T cells of PI-treated HIV-1+ patients. Methods: Forty PI-treated HIV-1+ patients were included (30 undergoing Lopinavir/ritonavir, 9 undergoing Atazanavir/ritonavir and 1 undergoing exclusively Atazanavir treatment). For each patients, the endogenous HIV-1 protease sequence, viral genotype and HLA class II typing were determined. We used the TEPITOPE algorithm to select promiscuous, multiple HLA-DR-binding peptides encoding 3 regions of HIV-1 HXB2 strain protease (HXB2 4-23, 45-64, and 76-95) and 32 additional peptides contained in the same regions, but encompassing the most frequent PI-induced mutations in Brazil. The 35 peptides were thus synthesized. Proliferative responses of CD4+ and CD8+ T cells against peptides were determined by the CFSE dilution assay. HLA class II binding assays were made to confirm the promiscuity of these peptides and evaluate their ability to bind the HLA molecules carried by each patient. Results: All tested peptides were recognized by at least one patient and proliferative responses of CD4+ and CD8+ T cells against at least one HIV-1 protease peptide were found in 78% and 75% patients, respectively. The third region (Protease 76-95) was the most frequently recognized. By comparing T-cell responses to HIV-1 endogenous protease sequences, we found that most patients failed to recognize identical peptides of those sequences, but recognized different variant peptides of the same region. Only seven patients responded to endogenous sequences. We found that several endogenous peptides that failed to be recognized showed no binding to the HLA alleles carried by that given patient, suggesting that mutations selected by immune pressure have led to escape of antigen presentation, as well as direct escape of the CD4+ T cell response. Alternatively, it could have been due to the presence of a different replicating virus in the plasma-since we only obtained proviral sequences. Conclusion: Wild-type and mutant HIV-1 protease epitopes recognized by CD4+ T cells were identified. We also found that most patients failed to recognize their endogenous protease sequences, while they recognized variant sequences. The recognition of non-endogenous sequences could hypothetically be a consequence of targeting a minor HIV-1 population; HERV protease, that contains regions of similarity with HIV-1 protease; or HIV-1 sequences present only in viremic partners. The failure to recognize endogenous sequences is most likely due to immune escape, either at the level of presentation or direct T cell recognition. This may have a pathophysiological consequence on evasion of T cell responses against protease and the fact that it has been considered traditionally a poorly antigenic HIV-1 protein.
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Livres sur le sujet "HIV-1 proteasi"

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March, Darren. Designing new antiviral drugs for AIDS : HIV-1 protease and its inhibitors. Austin : R.G. Landes, 1996.

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1930-, Kostka Vladimír, et International Congress of Biochemistry (14th : 1988 : Prague, Czechoslovakia), dir. Proteases of retroviruses : Proceedings of the Colloquium C 52, 14th International Congress of Biochemistry, Prague, Czechoslovakia, July 10-15, 1988. Berlin : W. de Gruyter, 1989.

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Harburn, James Jonathan. Novel steroidal inhibitors of HIV-1 protease. 1998.

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Kostka, Vladimir. Proteases of Retroviruses : Proceedings of the Colloquium C 52 14th International Congress of Biochemistry Prague, Czechoslovakia July 10-15, 1988. Walter De Gruyter Inc, 1989.

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Young, Benjamin. Classes of Antiretrovirals. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190493097.003.0019.

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Results of the randomized, international INSIGHT START clinical trial provide definitive proof of the benefit of antiretroviral therapy initiation in asymptomatic individuals with CD4+ counts greater than 500 cells/mm3. There are six different classes of antiretroviral agents: two types of reverse transcriptase inhibitors, two types of entry inhibitors, one class of inhibitors of HIV protease, and one class of inhibitors of HIV integrase. Combination antiretroviral therapy is recommended for all people living with HIV. The primary goal of combination antiretroviral therapy is to achieve viral suppression. Each antiretroviral class targets a unique step in the replication cycle of HIV-1.
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Livingston, Schuyler, Benjamin Young, Martin Markowitz, Poonam Mathur et Bruce L. Gilliam. HIV Virology. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190493097.003.0017.

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HIV is a member of the lentivirus subfamily of retroviruses. Two distinct groups of viruses are pathogenic in humans: HIV-1 and HIV-2. Both are transmitted sexually and known to cause immunodeficiency disease. HIV enters the cell through use of the CD4 receptor and chemokine co-receptors, primarily CCR5 and CXCR4. The viral genome is transcribed from RNA to DNA by reverse transcriptase and integrated into the host genome by integrase. The HIV genome encodes 15 proteins, comprising three categories: structural, regulatory, and accessory. After budding from the host cell, the virus matures into its infectious form through cleavage of viral precursor proteins by protease.
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Majid, Adrian, et Bruce L. Gilliam. Future Antiretrovirals, Immune-Based Strategies, and Therapeutic Vaccines. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190493097.003.0023.

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Highly active antiretroviral therapy remains the mainstay of treatment for patients chronically infected with HIV. Novel drugs, both within existing classes and new ones, are in various stages of development and testing. New medications within existing classes of antiretroviral agents are in clinical trials and will likely offer activity against resistant HIV-1 strains and provide alternatives for combination pill therapy. Novel therapeutics including oral attachment inhibitors and monoclonal antibody treatments continue to show efficacy against HIV-1 and progress in clinical trials. Tenofovir alafenamide is a prodrug that produces higher intracellular levels of tenofovir diphosphate with likely less renal and bone toxicity. Among traditional classes of HIV treatment, both doravirine (a non-nucleoside reverse transcriptase inhibitor) and cabotegravir (an integrase strand inhibitor) are newer agents with activity against resistant virus. Maturation inhibitors are a new class of treatment that block protease cleavage, leading to the release of an immature virion.
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Markgren, Per-Olof. Analysis of the Interaction Between HIV-1 Protease and Inhibitors : Applications for Drug Discovery (Comprehensive Summaries of Uppsala Dissertations, 511). Uppsala Universitet, 1999.

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Hulten, Johan. Cyclic Sulfamides As HIV-1 Protease Inhibitors : Synthesis, X-Ray Structure Analysis and Structure-Activity Relationship (Comprehensive Summaries of Uppsala ... from the Faculty of Pharmacy, 213). Uppsala Universitet, 1999.

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Andersson, Hans Ola. Structural-Aided Design of Antiviral Drugs : Application of the Method of HIV-1 Protease and Siv Reverse Transcriptase (Comprehensive Summaries of Uppsala ... the Faculty of Science and Technology, 477). Uppsala Universitet, 1999.

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Chapitres de livres sur le sujet "HIV-1 proteasi"

1

Weber, Irene T., Ying Zhang et Jozsef Tözsér. « HIV-1 Protease and AIDS Therapy ». Dans Viral Proteases and Antiviral Protease Inhibitor Therapy, 25–45. Dordrecht : Springer Netherlands, 2009. http://dx.doi.org/10.1007/978-90-481-2348-3_2.

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Geller, Maciej, Joanna Trylska et Jan Antosiewicz. « HIV-1 Protease and its Inhibitors ». Dans Theoretical and Computational Methods in Genome Research, 237–54. Boston, MA : Springer US, 1997. http://dx.doi.org/10.1007/978-1-4615-5903-0_18.

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Doyon, Louise, Robert Elston et Pierre R. Bonneau. « Resistance to HIV-1 Protease Inhibitors ». Dans Antimicrobial Drug Resistance, 477–92. Totowa, NJ : Humana Press, 2009. http://dx.doi.org/10.1007/978-1-59745-180-2_34.

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Sakurai, Mitsuya, Machiko Sugano, Susumu Higashida, Atsushi Kasuya, Shuichi Miyamoto, Hiroshi Handa, Tomoaki Komai, Ryuichi Yagi, Takashi Nishigaki et Yuichiro Yabe. « Synthesis of HIV-1 protease inhibitors ». Dans Peptide Chemistry 1992, 532–34. Dordrecht : Springer Netherlands, 1993. http://dx.doi.org/10.1007/978-94-011-1474-5_155.

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Wilderspin, Andrew, Duncan Gaskin, Risto Lapatto, Tom Blundell, Andrew Hemmings, John Overington, Jim Pitts et al. « Three-dimensional Structure and Evolution of HIV-1 Protease ». Dans Retroviral Proteases, 79–91. London : Macmillan Education UK, 1990. http://dx.doi.org/10.1007/978-1-349-11907-3_10.

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Debouck, Christine, Ingrid C. Deckman, Stephan K. Grant, Robert J. Craig et Michael L. Moore. « The HIV-1 Aspartyl Protease : Maturation and Substrate Specificity ». Dans Retroviral Proteases, 9–17. London : Macmillan Education UK, 1990. http://dx.doi.org/10.1007/978-1-349-11907-3_3.

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Peng, Cheng, Karin Moelling, Nancy T. Chang et Tse Wen Chang. « Functional Characterisation of HIV-1 gag-pol Fusion Protein ». Dans Retroviral Proteases, 55–62. London : Macmillan Education UK, 1990. http://dx.doi.org/10.1007/978-1-349-11907-3_7.

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Potempa, Marc, Sook-Kyung Lee, Richard Wolfenden et Ronald Swanstrom. « The Triple Threat of HIV-1 Protease Inhibitors ». Dans The Future of HIV-1 Therapeutics, 203–41. Cham : Springer International Publishing, 2015. http://dx.doi.org/10.1007/82_2015_438.

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Roller, P. P., M. Nomizu, S. W. Snyder, S. Oroszlan et J. B. McMahon. « Complementary peptides as inhibitors of HIV-1 protease ». Dans Peptides, 709–10. Dordrecht : Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-011-2264-1_283.

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Virgil, Scott C. « First-Generation HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS ». Dans Aspartic Acid Proteases as Therapeutic Targets, 139–68. Weinheim, Germany : Wiley-VCH Verlag GmbH & Co. KGaA, 2011. http://dx.doi.org/10.1002/9783527630943.ch6.

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Actes de conférences sur le sujet "HIV-1 proteasi"

1

Abdullah, Muhammad, Seher Ansar Khawaja et Muhammad Farooq. « HIV-1 Protease Cleavages ». Dans 2021 International Conference on Innovative Computing (ICIC). IEEE, 2021. http://dx.doi.org/10.1109/icic53490.2021.9692978.

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Barbosa, Karen Eduarda, et Jorge Alexandre Nogueira Santos. « ANÁLISE DO PAPEL DA ENZIMA HIV- 1 PROTEASE NO CICLO REPLICATIVO DO HIV ». Dans I Congresso Nacional de Microbiologia Clínica On-Line. Revista Multidisciplinar em Saúde, 2021. http://dx.doi.org/10.51161/rems/1197.

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Introdução: De acordo com os dados do boletim epidemiológico do Ministério da Saúde (2020), foram notificados 342.459 casos de infecção pelo vírus HIV no Brasil, entre os períodos de junho de 2007 a junho de 2020, demonstrando uma grande incidência da doença no país. Responsável pela depleção de linfócitos TDC4 +, o tratamento disponível consiste na terapia antirretroviral (HAART), baseada em inibidores de proteases entre os quais destaca-se a HIV-1 protease. Essa enzima é responsável pelo desenvolvimento do vírus, se constituindo num importante alvo farmacológico para o tratamento da AIDS. Objetivos: Nesse contexto, esse trabalho fará uma análise do papel da HIV-1 protease no ciclo de replicação do HIV. Materiais e Métodos: O presente trabalho tratou-se de um estudo descritivo que fez uso da base de dados do portal PUBMED, por meio da combinação das seguintes palavras chaves: HIV-1 protease, replication e AIDS. Filtrados os resultados de 2017 a 2021, obteve-se um total de 13 artigos para a recuperação dos dados. Resultados: O capsídeo viral possui as enzimas virais integrase, transcriptase reversa e proteases associadas ao genoma. A HIV-1 protease é um homodímero formado por 2 monômeros com 99 resíduos cada, e com o sítio formado pela tríade: Asp-25, Thr-26 e Gli-27. Localizada acima do sítio ativo da enzima, há a região flat que se abre para a entrada do substrato e também se fecha sobre ela quando complexada à substância. Ressalta-se que essa região também é importante para garantir a estabilidade da enzima. A clivagem das poliproteínas gag e pol, responsáveis pela formação das proteínas estruturais do vírus, ocorre quando dois resíduos de aspartato ligam-se a uma molécula de água e promovem a hidrólise do substrato. Tal clivagem permite um rearranjo das cadeias que agora se tornam funcionais e originam partículas infecciosas que poderão ser liberadas no citoplasma e progredir com a infecção. Conclusões: Essa enzima é relevante para o entendimento do ciclo replicativo do HIV, uma vez que se relaciona com a produção de proteínas virais funcionais. Sua inibição dá origem a partículas virais imaturas e por isso a enzima se constitui em um dos alvos para inibição.
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Farache Trajano, Luiza, Rebecca Moore et Quentin Sattentau. « The Presence of Chemical Cross-Linking Stabilises HIV-1 Envelope Glycoprotein Trimer Antigens in a Model of Intramuscular Immunisation ». Dans Building Bridges in Medical Science 2021. Cambridge Medicine Journal, 2021. http://dx.doi.org/10.7244/cmj.2021.03.001.4.

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Background: The HIV-1 envelope glycoprotein (Env) is the target of antigen design for antibody- based vaccination. In 2019, four trimeric Env vaccines entered an experimental trial: ConM, ConS, and their cross-linked counterparts. The trimers were formulated with MPLA adjuvant. Studies have demonstrated that adjuvants trigger neutrophil infiltration. Neutrophils activate and degranulate releasing proteases, namely elastase and cathepsinG. Aims: To assess the stability and immunogenicity of these vaccines in the presence of adjuvant- recruited neutrophils and their proteolytic enzymes. Methods: Trimers were incubated with commercially-sourced proteases. To analyse stability, samples were reduced, denatured and separated using gel electrophoresis. To assess antibody binding, a trimer-protease incubation was followed by an ELISA. To establish more physiologically relevant conditions, harvested neutrophils were exposed to various adjuvants. The supernatant, shown to contain elastase, was incubated alongside the vaccines. The reducing and denaturing gels, as well as the ELISA, was repeated. Results: Gel analysis revealed that un-crosslinked trimers underwent significant digestion whereas cross-linking conferred enhanced stability. In the presence of neutrophil-sourced protease-containing-supernatant, trimers displayed resistance to digestion. The differential stability profile of Env trimers when exposed to commercially sourced compared to supernatant- derived proteases may be due to the inhibitory effect of human serum on elastase. Antibody epitopes were maintained in vitro. Conclusion: The vaccine antigens are sensitive to enzymatic degradation. This is reduced by cross-linking and human serum.
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Yu, Xiaxia, Irene Weber et Robert Harrison. « Sparse Representation for HIV-1 Protease Drug Resistance Prediction ». Dans Proceedings of the 2013 SIAM International Conference on Data Mining. Philadelphia, PA : Society for Industrial and Applied Mathematics, 2013. http://dx.doi.org/10.1137/1.9781611972832.38.

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Kumar, Sunil, Rajni Garg, Srinivas R. Alla, Xiaoyu Zhang et Vivek K. Jalahalli. « 3D-Shape analysis of the HIV-1 protease ligand binding site ». Dans 2008 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology (CIBCB 2008). IEEE, 2008. http://dx.doi.org/10.1109/cibcb.2008.4675772.

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Peng, Xinzhan, Daniel R. Draney et William M. Volcheck. « Quenched near-infrared fluorescent peptide substrate for HIV-1 protease assay ». Dans Biomedical Optics 2006, sous la direction de Samuel Achilefu, Darryl J. Bornhop et Ramesh Raghavachari. SPIE, 2006. http://dx.doi.org/10.1117/12.669174.

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You, Liwen, et Intelligent Systems Lab. « DETECTION OF CLEAVAGE SITES FOR HIV-1 PROTEASE IN NATIVE PROTEINS ». Dans Proceedings of the Conference CSB 2006. PUBLISHED BY IMPERIAL COLLEGE PRESS AND DISTRIBUTED BY WORLD SCIENTIFIC PUBLISHING CO., 2006. http://dx.doi.org/10.1142/9781860947575_0031.

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Onuku, Raphael, Ngozi Nwodo et Akachukwu Ibezim. « Repurposing Drugs to Find HIV-1 Protease Inhibitors : A Virtual Study ». Dans MOL2NET'21, Conference on Molecular, Biomedical & Computational Sciences and Engineering, 7th ed. Basel, Switzerland : MDPI, 2021. http://dx.doi.org/10.3390/mol2net-07-12067.

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Kim, Gilhan, Yeonjoo Kim et Hyeoncheol Kim. « Feature Selection using Multi-Layer Perceptron in HIV-1 Protease Cleavage Data ». Dans 2008 International Conference on Biomedical Engineering And Informatics (BMEI). IEEE, 2008. http://dx.doi.org/10.1109/bmei.2008.169.

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Nishimura, R. H. V., F. T. Toledo et G. C. Clososki. « Preparation of New Magnesium Carbenoids Aiming Inhibitors of HIV-1 Protease Synthesis ». Dans 15th Brazilian Meeting on Organic Synthesis. São Paulo : Editora Edgard Blücher, 2013. http://dx.doi.org/10.5151/chempro-15bmos-bmos2013_2013913171326.

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