Дисертації з теми "HIV-1 proteasi"
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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.
Повний текст джерелаDemitri, 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.
Повний текст джерелаDurante 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
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.
Повний текст джерелаSchaal, 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/.
Повний текст джерелаHarburn, James J. "Novel steroidal inhibitors of HIV-1 protease." Thesis, Loughborough University, 1998. https://dspace.lboro.ac.uk/2134/14701.
Повний текст джерелаMartins, 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/.
Повний текст джерелаDespite 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.
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/.
Повний текст джерелаPersson, 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.
Повний текст джерелаFelaktigt tryckt som Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 724
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.
Повний текст джерелаCataloged 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
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/.
Повний текст джерелаIntroduction: 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.
Ax, Anna. "Cyclic Sulfamide HIV-1 Protease Inhibitors : Design, Synthesis and Modelling." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5803.
Повний текст джерелаKenway, O. A. "Molecular dynamics simulations of complex systems including HIV-1 protease." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19485/.
Повний текст джерелаWatson, S. J. "Molecular dynamics simulations of HIV-1 protease complexed with saquinavir." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/19060/.
Повний текст джерелаTukulula, Matshawandile. "The design and synthesis of novel HIV-1 protease inhibitors." Thesis, Rhodes University, 2009. http://eprints.ru.ac.za/1563/.
Повний текст джерелаAhlsén, Göran. "Structure-activity and resistance studies of HIV-1 protease inhibitors /." Online version, 2000. http://bibpurl.oclc.org/web/30656.
Повний текст джерелаCamp, Nicholas Paul. "Design and synthesis of inhibitors for the HIV-1 protease." Thesis, University of St Andrews, 1994. http://hdl.handle.net/10023/14309.
Повний текст джерелаMelo, Nadja Rodrigues de. "Caracterização de leveduras de cavidade oral de crianças infectadas pelo HIV-1, antes e durante o uso de inibidor de protease." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311087.
Повний текст джерелаTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-07T08:42:49Z (GMT). No. of bitstreams: 1 Melo_NadjaRodriguesde_D.pdf: 2013115 bytes, checksum: 52276d586f25b6b0ea07f41ad6a754df (MD5) Previous issue date: 2006
Resumo: O presente estudo caracterizou a flora oral de Candida em 52 crianças infectadas pelo HIV-1 em dois períodos, definidos como período I antes da introdução de inibidores de protease no esquema de terapia antiretroviral para HIV-1 e período II após a introdução de inibidores de protease. Comparou-se as espécies de Candida identificadas nos períodos I e II. Isolados do períodos I foram identificados e as crianças em sua maioria (80%) estavam colonizadas por C. albicans. Redução no percentual de colonização por C. albicans de 80% para 52%, nos períodos I e II respectivamente, sugere mudança na colonização oral por Candida após a introdução da terapêutica com inibidores de protease HIV (IP). Destaca-se particularmente o aumento da incidência de isolados Não¿albicans (p=0.005) no período II. No período I haviam 8 crianças que estavam colonizadas por espécies Não-albicans e no período II haviam 20 crianças colonizadas com isolados Não-albicans. Investigou-se a prevalência de C. dubliniensis na família de uma das crianças que estava colonizada por esta levedura. Do total de 52 crianças 38.4% mostraram manifestação oral associada a colonização por Candida. Observou-se alta sensibilidade dos isolados aos agentes antifúngicos testados, mas 4% dos isolados exibiram resistência ao fluconazol. Documentou-se resistência cruzada entre agentes antifúngicos em isolado de Candida albicans em uma criança infectada pelo HIV-1 não previamente exposta a azoles. Um isolado de C. tropicalis mostrou baixa susceptibilidade ao fluconazol (MIC = 64 µg/ml) (1). O presente estudo revelou mudança significativa na colonização oral por Candida em crianças infectadas pelo HIV-1 sob terapia HAART (Highly Active Antiretroviral Therapy). Houve alta diversidade de espécies de Candida, com emergência de espécies Não-albicans após o uso de Inibidores de protease
Abstract: This study characterized the Candida oral flora from 52 Brazilian HIV 1-infected children, comparing the Candida species identified in two periods before (PI) and under (PII) the introduction of the HIV Protease Inhibitor therapy. The majority (80%) of the children from the PI group were colonized by C. albicans. Children in the PII (52%) were colonized by C. albicans and 28% of them carried on mixed colonization (C. albicans and Non¿albicans isolates). Therefore when we compared the periods I and II, after the inhibitor protease usage there was an important decrease in the percentile of colonization for C. albicans of 80% to 52%, suggesting an important change of the Candida oral colonization after the HIV protease inhibitors introduction. Particularly with increase of the Non-albicans isolates incidence (p=0.005) in the period II. In PI there were 8 children that were colonized by Non-albicans species and in the PII there were 20 children colonized with Non¿albicans isolates. Rare Candida species were identified, particularly we investigated the C. dubliniensis prevalence in a HIV-infected child¿s family. Of 52 children in this study 20 (38.4%) of them showed oral lesions associated to the Candida colonization. In spite of the high susceptibility of the isolates to the antifungal agents tested in this study, 4.4% (n=2) exhibited resistance to the fluconazole. One of the isolates was C. albicans from a HIV-infected child not prior exposure to azoles, which showed antifungal cross-resistance. One C. tropicalis isolate has shown low susceptibility to fluconazol (MIC = 64 µg/ml). This study was succeeded in showing the inhibitory effect of ritonavir on a single hyphae tip growth of C. albicans. The present investigation revealed a significative change of the Candida oral colonization in Brazilian HIV-infected children under HAART, high diversity of Candida species and Non-albicans species emergence after IP usage
Doutorado
Pediatria
Doutor em Saude da Criança e do Adolescente
Junior, Mario Sanches Matilde. "Resolução estrutural cristalográfica de proteases de HIV-1 de subtipos brasileiros e estudos estruturais da l-asparginase de Escherichia coli." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-07052014-150826/.
Повний текст джерелаOne of the major problems faced in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance, as well as viral subtypes naturally more liable to development of therapeutic failure. In this work we solved the crystal structure of four HIV-1 proteases complexed with the universal C2 symmetry-based inhibitor TL-3. These proteases where obtained from patients with AIDS: one of the subtype B wild type (Bwt), one of the subtype F wild type (Fwt), and a mutant of each subtype (Bmut and Fmut), these last two out of patients showing therapeutic failure. The proteins were produced by Escherichia coli bacteria heterologous expression, purified out of the inclusion bodies, and refolded. The collected diffraction data were processed to 2.1 A resolution for the Bwt:TL-3 complex, 1.75 A for Bmut:TL-3, 2.1 A for Fwt:TL-3 and 2.8 A for Fmut:TL-3. These data were initially processed in the P6122 space group and latter reprocessed in P6i. The four structures were solved by molecular replacement using a published HIV-1 protease structure as a model. The structural analysis shown that the TL-3 inhibitor binds in a similar fashion in the active site of all four structures. On the proteases Bmut and Fmut the mutation V82A causes a repacking of the SI\' pocket which rerranges the inhibitor\'s side chain at P1\' subsite. Our analysis further indicate that some polymorphic substitutions between subtypes B and F could lead to a stabilization of naturally flexible regions on subtype F proteases, creating a intrinsically less active resistant enzyme. On the proteases Fwt and Fmut the polymorphic substitution M36I leads to the displacement of the loop between residues 35-41, which would cause a flexibility loss of the flaps and of the loop 76-83 in the active site. Our comparisons further indicate that the polymorphic substitution L89M on non-B subtypes could be equivalent to the L90M resistance mutation on subtype B proteases. Lastly, based on these structural data we were able to suggest a few structural modifications on the TL-3 inhibitor that could furnish a more potent inhibitor. On this thesis we also present the data of structural solution and analysis of the Escherichia coli L-asparaginase solved at 1.95 A resolution in C2 space group. Based on structural and kinetical data we proposed a general reaction mechanism for amidohidrolases, which include L-asparaginases, involving the formation of two catalytic triads Thr-Tyr-Glu and Thr-Lys-Asp, which acounts for the two threonines in the active site. Our cavity volume analysis of three amidohidrolases also indicate that the increasing in the L-glutaminase activity in some enzimes is directly proportional to the increase in the cavity volume.
Nguyen, Anh Thu. "Effects of the HIV-1 protease inhibitor ritonavir on preadipocyte differentiation." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9001.
Повний текст джерелаKolli, Madhavi. "Co-evolution of HIV-1 Protease and its Substrates: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/455.
Повний текст джерелаSadiq, S. K. S'ad. "Molecular dynamics simulation studies of drug resistance in HIV-1 protease." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445831/.
Повний текст джерелаGreene, Shaquita T., and Ying Zhang. "HIV-1 PR P51 Mutant Complex Formation with Inhibitors." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_hontheses/4.
Повний текст джерелаRashamuse, Thompho Jason. "Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors." Thesis, Rhodes University, 2008. http://eprints.ru.ac.za/1332/.
Повний текст джерелаRose, Nathan Rolf. "Synthesis of novel coumarin derivatives as potential inhibitors of HIV-1 protease." Thesis, Rhodes University, 2007. http://hdl.handle.net/10962/d1007220.
Повний текст джерелаKMBT_363
Adobe Acrobat 9.54 Paper Capture Plug-in
Herpoldt, Karla-Luise. "Multivalent biological interactions for the detection and inhibition of HIV-1 protease." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/29440.
Повний текст джерелаFerreira, Leonardo Luiz Gomes. "Estudos das relações quantitativas entre a estrutura e atividade de uma série de inibidores da protease do vírus HIV-1." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-17092008-151521/.
Повний текст джерелаThe Human Immunodeficiency Virus Type 1 Protease (HIV-1 PR, EC 3.4.23.16) is a macromolecular target of great importance for the therapy of the Acquired Immunodeficiency Syndrome (AIDS). Major pharmaceutical companies around the world concentrate several efforts on studies concerning this enzyme, which since saquinavir (Invirase®) reached the market in 1995, has maintained its status as a fundamental target for anti-HIV drug discovery. HIV-1 protease has a rich history of enormous success in the drug discovery and development process. The strong multidisciplinary character of modern Medicinal Chemistry supplies an arsenal of useful rational strategies for the design of new drugs. One such technology is quantitative structure-activity relationships (QSAR), which has been successfully applied in a number of settings. QSAR studies aim to identify and quantify the relations between structure and activity of series of bioactive molecules organized within standard data sets. In the present master\'s dissertation, 2D and 3D QSAR studies were performed employing the hologram QSAR (HQSAR) and comparative molecular field analysis (CoMFA) techniques, respectively, in order to generate predictive models for a large set of HIV-1 PR inhibitors. The final models along with the information obtained from the 2D contribution and 3D contour maps should be useful in the design of new inhibitors with increased potency and selective within the chemical diversity of the data set.
Cherry, Elana. "Trans-dominant negative inhibition of human immunodeficiency virus type 1 replication by expression of protease-reverse transcriptase fusion proteins." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0019/NQ50069.pdf.
Повний текст джерелаSutherland, K. "Contribution of Gag and protease to variation in susceptibility to protease inhibitors between different strains of HIV-1." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1455362/.
Повний текст джерелаÖsterberg, Fredrik. "Exploring Ligand Binding in HIV-1 Protease and K+ Channels Using Computational Methods." Doctoral thesis, Uppsala universitet, Strukturell molekylärbiologi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6167.
Повний текст джерелаÖsterberg, Fredrik. "Exploring ligand binding in HIV-1 protease and K+ channels using computational methods /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6167.
Повний текст джерелаLindgren, Maria T. "Exploring Inhibitors of HIV-1 Protease : Interaction Studies with Applications for Drug Discovery." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4655.
Повний текст джерелаTie, Yunfeng. "Crystallographic Analysis and Kinetic Studies of HIV-1 Protease and Drug-Resistant Mutants." Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/chemistry_diss/2.
Повний текст джерелаWright, D. W. "Molecular dynamics simulation of drug resistance in HIV-1 protease and reverse transcriptase." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1331997/.
Повний текст джерелаHaqqani, Aiman Aafreen. "DEVELOPMENT OF A QUANTITATIVE UNDERSTANDING OF HIV-1 PROTEASE PROCESSING USING MASS SPECTROMETRY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1548433551709353.
Повний текст джерелаFanelli, Roberto. "Design and synthesis of new peptidomimetics as potential inhibitors of HIV-1 protease." Paris 11, 2010. http://www.theses.fr/2010PA114855.
Повний текст джерелаBeing HIV-1 protease responsible for the post-translational processing of the viral polyproteins and the subsequent generation of the structural and functional proteins, it is an important target for the treatment of AIDS. HIV-1 protease is an aspartyl protease active as an homodimer. Every single chain is built of 99 amino acids and the active site is at the interface between the two monomeric units. The commercially available protease inhibitors target the active site but several mutations within or outside the active site led to the emergence of resistance to these compounds. This thesis deals with the design and synthesis of peptides and peptidomimetics as potential inhibitors of HIV-1 protease that can circumvent drug resistance and that can be alternatives to active site PR inhibitors. Two different approaches were applied to reach our target. The first one, described in chapter 2, deals with the folding of the protease monomer that proceeds following a hierarchical succession of events starting from the formation of local elementary structures (LES), which contain highly conserved amino acids. The interaction between two complementary LES represents the first step of the folding process. Since these LES are so important for the protein, the virus can not afford their mutation. We describe here the synthesis of small peptides with the same sequence as one of these critical regions (p-LES) and of peptidomimetics analogues to the p-LES that could bind to the complementary region preventing the correct folding. CD studies of interaction between synthesized peptides and native sequence of the protease are presented. The second approach, described in chapter 3, consists in the design and synthesis of compounds mimetics of the terminal -sheet of the HIV-1 protease. The dimeric form of HIV-1 protease is stabilized by the antiparallel -sheet formed between the C- and N-terminal regions of the protein. Constrained molecular tongs based on a naphtalene scaffold in which peptidomimetic strands are attached through a carboxylpropyl link disrupt the dimeric enzyme with loss of activity. We are now concerned in decreasing the peptidic character and increasing the hydrosolubility of the molecular tongs. For that purpose, we have conceived two different strategies: 1) the synthesis of new peptidomimetic strands with increased hydrophilicity and 2) the introduction of hydrophilic groups on the scaffold mainly via metal-catalyzed cross coupling reactions. We describe here the synthesis and the biological activity against wild-type and mutated HIV-1 protease of these new molecular tongs
Molefe, Duduzile Mabel. "Studies directed towards the synthesis of chromone carbaldehyde-derived HIV-1 protease inhibitors." Thesis, Rhodes University, 2008. http://hdl.handle.net/10962/d1015542.
Повний текст джерелаFanelli, R. "DESIGN AND SYNTHESIS OF NEW PEPTIDOMIMETICS AS POTENTIAL INHIBITORS OF HIV-1 PROTEASE." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150204.
Повний текст джерелаEkegren, Jenny. "Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6737.
Повний текст джерелаAdrian, Meredith Jenny. "Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-1." Doctoral thesis, Stockholms universitet, Institutionen för organisk kemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-29773.
Повний текст джерелаAt the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Submitted. Paper 2: Submitted. Paper 3: Manuscript.
Medeiros, Melissa Soares. "Genotyping and antiretroviral resistance profile test from HIV-1 samples in patients with therapeutic failure from CearÃ." Universidade Federal do CearÃ, 2006. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=39.
Повний текст джерелаIntroduction: Genotypic testing for HIV-1 drug resistance is useful for selecting antiretroviral drugs for patients developing treatment failure. O melhor entendimento da sua interpretaÃÃo facilitarà sua utilizaÃÃo como ferramenta mÃdica na terapÃutica do HIV. The optimal understanding of its interpretation will give an important tool for HIV treatment. Objective: To identify common combinations of resistance mutations and antiretroviral resistance profile. Methods: Between April 2002 and March 2004, 101 protease and reverse transcriptase (RT) sequences were determined for HIV-1 isolates from patients who were failing antiretroviral therapy. Resistance profile was obtained by Stanford program. Results: male were 76.2%, median age 38 years, CD4 media was 279.21 cells/mm3 and Viral load 4.49 log. Total of 31 mutational patterns were detected to protease inhibitor (IP), 49 to nucleoside RT inhibitor (NRTI), and 17 to nonnucleoside RT inhibitor (NNRTI). K65R was detected in 5.9% isolates. The most frequent mutations were L90M, M184V and K103N to IP, NRTI and NNRTI respectively. The main mutational patterns accounted for 49% of mutant sequences to IP, 38.5% to ITRN accounted and 40,9% to NNRTI. Patients with three or more therapeutic failure had worst resistance profile to all IP except for Lopinavir, and NRTI except for Tenofovir. High resistance to Lamivudine and NNRTI were independent of failure quantity. Conclusion: The best susceptibility was found to Lopinavir at IPâs class and to Tenofovir at ITRNâs. The main mutational patterns to IP, ITRN and NNRTI represented almost half of all patterns found.
A Genotipagem està sendo usada como mÃtodo para guiar a seleÃÃo de antiretrovirais em pacientes com falha terapÃutica. O melhor entendimento da sua interpretaÃÃo facilitarà sua utilizaÃÃo como ferramenta mÃdica na terapÃutica do HIV. Objetivo: Avaliar o perfil de resistÃncia aos antiretrovirais e identificar padrÃes mutacionais das seqÃÃncias de protease e TR do HIV-1. MÃtodos: Foram estudadas as sequÃncias de genes da protease e TR isoladas de 101 amostras de pacientes com HIV-1 em falha terapÃutica, entre abril/2002 a marÃo/2004, atravÃs de Genotipagem realizadas no CearÃ. O Banco de dados de Stanford foi utilizado para avaliaÃÃo de resistÃncia e SPSS versÃo 11 e Epi Info versÃo 6 para anÃlise estatÃstica. Resultados: Sexo masculino 76,2%, mediana de idade 38 anos, CD4 mÃdio de 279,21 cells/mm3 e Carga Viral 4.49 log. Na classe de Inibidores de Protease (IP) 31 padrÃes mutacionais foram encontrados, nos inibidores da transcriptase reversa anÃlogos de nucleosÃdeos (ITRN) 49 e para inibidores da transcriptase reversa nÃo anÃlogos de nucleosÃdeos (ITRNN) 17. As mutaÃÃes mais frequentes foram L90M, M184V e K103N para IP, ITRN e ITRNN espectivamente. A K65R foi detectada em 5,9% dos isolados. TrÃs ou mais falhas terapÃuticas apresentaram maior perfil de resistÃncia para todos os IPs exceto para Lopinavir, e para todos os ITRNs exceto para Tenofovir. Os seis principais padrÃes mutacionais para IPs equivaleram a 49% das sequÃncias, para ITRNs a 38,5%, e para ITRNNs os dois principais padrÃes corresponderam a 40,9%. Foram encontrados altos Ãndices de resistÃncia para ITRNNs independente da quantidade de falhas terapÃuticas. ConclusÃo: Nos IPs a menor resistÃncia encontrada foi ao Lopinavir e nos ITRNs ao Tenofovir. Os principais padrÃes mutacionais para IPs, ITRNs e ITRNNs representaram quase metade de todos os padrÃes de resistÃncia encontrados.
Phenix, Barbara N. "A new role for human immunodeficiency virus (HIV)-1 protease inhibitors: Suppression of apoptosis." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/29000.
Повний текст джерелаMengistu, Netsanet. "Ethyl Pyruvate and HIV-1 Protease Inhibitors in Drug Discovery of Human African Trypanosomiasis." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-180770.
Повний текст джерелаRagland, Debra A. "The Structural Basis for the Interdependence of Drug Resistance in the HIV-1 Protease." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/879.
Повний текст джерелаHOLANDA, Luiz Henrique Campos. "Análise conformacional da enzima protease do HIV-1 relacionada à resistência ao inibidor Nelfinavir." Universidade Federal do Pará, 2017. http://repositorio.ufpa.br/jspui/handle/2011/9249.
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CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
O Vírus da imunodeficiência humana (HIV), causador da síndrome da imunodeficiência adquirida (AIDS), é um retrovírus que possui glicoproteínas altamente virulentas que invadem o linfócito TCD4+ através de seus receptores CCR4 e CXCR5. O ciclo biológico do HIV é mediado pelas enzimas protease, transcriptase e integrase. A HIV-1 protease é uma enzima que está presente na fase final do ciclo biológico, onde ocorre a maturação do vírus e é um importante alvo farmacológico. O objetivo principal deste projeto é verificar os efeitos das mutações D30N, I84A e M46I na enzima protease HIV-1 e na formação do complexo com o inibidor nelfinavir através de técnicas de dinâmica molecular e bioinformática. Os resultados baseados nas análises estruturais mostraram diferenças estruturais entre os sistemas estudados. O sistema 1OHR apresentou uma conformação fechada, os sistemas D30N e D30N_I84A_M46I apresentaram conformação semi-aberta e o sistema D30N_I84A apresentou conformação aberta, em que o último apresentou menor valor de energia livre e maior instabilidade nas análises de RMSD, porém a maior flutuação de resíduos de aminoácidos. As análises teóricas mostraram a importância na resistência da dupla mutação D30N_I84A e a capacidade de reestruturação conformacional da mutação M46I e capacidade catalítica.
The Human Immunodeficiency Virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), is a retrovirus that has highly virulent glycoproteins that invade the CD4 + T lymphocyte through its CCR4 and CXCR5 receptors. The biological cycle of HIV is mediated by the protease, transcriptase and integrase enzymes. HIV-1 protease is an enzyme that is present in the final phase of the biological cycle, where virus maturation occurs, and is an important pharmacological target. The main objective of this project is to verify the effects of the D30N, I84A and M46I mutations on the HIV-1 protease enzyme and the complex formation with the nelfinavir inhibitor through molecular dynamics and bioinformatics techniques. The results based on the structural analyzes showed structural differences between the studied systems. The 1OHR system presented a closed conformation, the systems D30N and D30N_I84A_M46I presented semi-open conformation and the D30N_I84A system presented open conformation, in which the latter presented lower free energy value and greater instability in the RMSD analyzes, however the greater flotation of residues Of amino acids. The theoretical analyzes showed the importance in the resistance of the double mutation D30N_I84A and the conformational restructuring capacity of the M46I mutation and catalytic capacity.
Ragland, Debra A. "The Structural Basis for the Interdependence of Drug Resistance in the HIV-1 Protease." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/879.
Повний текст джерелаHohlfeld, Konrad. "Disubstituted BIS-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors." Thesis, University of Southampton, 2011. https://eprints.soton.ac.uk/193149/.
Повний текст джерелаMathu, Alexander Muchugia Nganga. "Structural analysis of effects of mutations on HIV-1 subtype C protease active site." Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004073.
Повний текст джерелаMurzycki, Jennifer E. "Probing Protein Dynamics Through Mutational and Computational Studies of HIV-1 Protease: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/166.
Повний текст джерелаCai, Yufeng. "Energetic and Dynamic Analysis of Inhibitor Binding to Drug-Resistant HIV-1 Proteases: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/448.
Повний текст джерелаGarner, Joanne Clare. "Site directed mutagenesis, autoprocessing and inhibitor studies on the retroviral protease of the human immunodeficiency virus type-1." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302318.
Повний текст джерела