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Artykuły w czasopismach na temat "NELFINAVIR RESISTANCE"
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Besse, Andrej, Lenka Besse, Sara C. Stolze, Amin Sobh, Esther A. Zaal, Alwin J. van der Ham, Mario Ruiz i in. "Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity". Blood 136, Supplement 1 (5.11.2020): 11. http://dx.doi.org/10.1182/blood-2020-136253.
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INTRODUCTION Nelfinavir is a highly lipophilic, first generation HIV-protease inhibitor (HIV-PI) approved for HIV treatment. It has largely been replaced by next-generation HIV-PI with increased specificity and efficacy for HIV therapy, partly reflecting the significant rate of the off-target activity of nelfinavir. Increasing preclinical and clinical evidence shows that nelfinavir has broad anti-cancer activity as a single agent and in combination, potentially related to its off-target activity in mammalian cells. Nelfinavir is particularly effective in the treatment of proteasome inhibitor-refractory multiple myeloma (MM), where the combination of nelfinavir+bortezomib+dexamethasone yielded an overall response rate (ORR, PR or better) > 65% in a Phase II clinical trial. The targets and molecular mechanism of action of nelfinavir in MM are unknown. This hampers both, a rational clinical repositioning and development of nelfinavir as antineoplastic drug, as well as the design, synthesis and testing of next generation nelfinavir-like compounds with optimized antineoplastic activity and improved specificity or pharmacologic properties. We therefore aimed to take an unbiased target-identification approach to identify molecular targets of nelfinavir in human malignant cells and link them to cell biological processes and mechanisms that mediate sensitivity or resistance to nelfinavir treatment. METHODS Proteome-wide affinity-purification of targets binding the nelfinavir active site was combined with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir and candidate genetic contributors affecting nelfinavir cytotoxicity. Multiple intracellular reporter systems including RUSH system, ATP/ADP constructs; FRAP microscopy, Seahorse measurements, flow cytometry, qPCR, metabolic labelling, lipidomics and viability assays were used to dissect functional alterations in pathways related to nelfinavir targets. RESULTS We identified a common set of proteins interacting specifically with the active site of nelfinavir. These proteins are embedded in intracellular, lipid-rich membranes of mitochondria (VDAC1,2,3, ANT2), endoplasmic reticulum (BCAP31, CANX, SRPRB) and nuclear envelope (PGRMC2) and are consistent across multiple cancer cell types. ADIPOR2, a key regulator gene of membrane lipid fluidity, was identified as a key nelfinavir resistance gene, while genes involved in fatty acids (FAs) and cholesterol metabolism, vesicular trafficking and mitochondria biogenesis are candidate sensitivity genes. We further show that via binding to proteins in lipid-rich membranes nelfinavir affects membrane composition and reduces membrane fluidity, leading to induction of FAs synthesis and the unfolded protein response (UPR). Via its structural interference with membrane fluidity, nelfinavir impairs the function and mobility of a diverse set of membrane-associated proteins and processes, such as glucose flux and processing, mitochondria respiration, energy supply, transmembrane vesicular transport and ABCB1-mediated drug efflux, as we show in different reporter systems in live MM cells. These functional effects are prevented by addition of metabolically inert lipids to be incorporated in membranes, supporting a direct structural activity of nelfinavir. The adaptive biology of proteasome inhibitor (PI)-resistant myeloma relies on metabolic reprogramming and changes in lipid composition, drug export and down-modulation of the UPR. Modulation of membrane fluidity and depletion of FAs/cholesterol is synergistic with proteasome inhibitors in PI-resistant MM. Thus, the mechanism of action of nelfinavir perfectly matches with the biology of PI-resistant MM, serving as a molecular rational for its significant clinical activity. CONCLUSION We here demonstrate in vitro that the activity of nelfinavir against MM cells is triggered through changes in lipid metabolism and the fluidity of lipid-rich membranes. Pharmacologic targeting of membrane fluidity is a novel, potent mechanism to achieve anti-cancer activity, in particular against PI-refractory MM. This mechanism explains the clinical activity of nelfinavir in MM treatment as well as the key side effects of nelfinavir during antiretroviral therapy. Disclosures No relevant conflicts of interest to declare.
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Fassmannová, Dominika, František Sedlák, Jindřich Sedláček, Ivan Špička i Klára Grantz Šašková. "Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma". Cancers 12, nr 5 (25.04.2020): 1065. http://dx.doi.org/10.3390/cancers12051065.
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Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir’s effectiveness in the treatment of multiple myeloma.
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Patick, A. K., M. Duran, Y. Cao, D. Shugarts, M. R. Keller, E. Mazabel, M. Knowles, S. Chapman, D. R. Kuritzkes i M. Markowitz. "Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from Patients Treated with the Protease Inhibitor Nelfinavir". Antimicrobial Agents and Chemotherapy 42, nr 10 (1.10.1998): 2637–44. http://dx.doi.org/10.1128/aac.42.10.2637.
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ABSTRACT Nelfinavir mesylate (formerly AG1343) is a potent and selective inhibitor of human immunodeficiency virus (HIV) protease approved for the treatment of individuals infected with HIV. Nucleotide sequence analysis of protease genes from plasma HIV type 1 (HIV-1) RNA revealed a unique aspartic acid (D)-to-asparagine (N) substitution at residue 30 (D30N) in 25 of 55 patients treated with nelfinavir for a median of 13 weeks. Although the appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes (e.g., at residues 35, 36, 46, 71, 77, and 88), genotypic changes associated with phenotypic resistance to other protease inhibitors were not observed (e.g., at residues 48, 50, 82, and 84) or were only rarely observed (e.g., at residue 90). In phenotypic assays, viral isolates with high-level resistance to nelfinavir remained susceptible to indinavir, saquinavir, ritonavir, and amprenavir (formerly VX-478/141W94). Similar results were observed in phenotypic assays utilizing HIV-1 NL4-3, which contained the D30N substitution alone or in combination with substitutions at other residues (e.g., residues 46, 71, and 88). These data indicate that the initial pathway of resistance to nelfinavir is unique and suggest that individuals failing short courses of nelfinavir-containing regimens may respond to regimens containing other protease inhibitors.
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Yerly, Sabine, Martin Rickenbach, Matei Popescu, Patrick Taffe, Charles Craig, Luc Perrin, M. Battegay i in. "Drug Resistance Mutations in HIV-1-Infected Subjects during Protease Inhibitor-Containing Highly Active Antiretroviral Therapy with Nelfinavir or Indinavir". Antiviral Therapy 6, nr 3 (1.04.2000): 185–89. http://dx.doi.org/10.1177/135965350100600304.
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Objectives The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir. Study design and methods The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment. Responders with subsequent treatment failure (HIV-RNA >1000 copies/ml, bordered by HIV-RNA >400 copies/ml) were selected for genotypic analysis. Results Initial treatment response, maintenance of response and subsequent virological failure were observed at a comparable frequency in 1143 nelfinavir and 1555 indinavir subjects. Of the treatment-naive patients, 13% who took nelfinavir and 16% who took indinavir had HIV-RNA >1000 copies/ml at least once. These values increased to 24 and 27%, respectively, for reverse transcriptase inhibitor-experienced subjects. Genotypic analysis in a subset of subjects with virological failure identified 30N as the only primary mutation in the nelfinavir subjects (8 out of 21, 38%) whereas isolated or combined 82A/T and 46I/L mutations were detected in the indinavir subjects (9 out of 20, 45%). Conclusions In this population of previously PI-naive subjects, the rate of virological failure and the frequency of resistance mutations at the time of virological failure were comparable in subjects receiving nelfinavir- or indinavir-containing HAART. In nelfinavir subjects, 30N was the only primary mutation whereas isolated or combined 82A/T and 46I/L mutations were detected in indinavir subjects.
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Kachko, Ilana, Adva Maissel, Livnat Mazor, Ronit Ben-Romano, Robert T. Watson, June C. Hou, Jeffrey E. Pessin, Nava Bashan i Assaf Rudich. "Postreceptoral Adipocyte Insulin Resistance Induced by Nelfinavir Is Caused by Insensitivity of PKB/Akt to Phosphatidylinositol-3,4,5-Trisphosphate". Endocrinology 150, nr 6 (29.01.2009): 2618–26. http://dx.doi.org/10.1210/en.2008-1205.
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Adipocyte insulin resistance can be caused by proximal insulin signaling defects but also from postreceptor mechanisms, which in large are poorly characterized. Adipocytes exposed for 18 h to the HIV protease inhibitor nelfinavir manifest insulin resistance characterized by normal insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate proteins, preserved in vitro phosphatidylinositol 3-kinase (PI 3-kinase) assay activity but impaired activation of PKB/Akt and stimulation of glucose uptake. Here we aimed to assess whether impaired PKB/Akt activation is indeed rate limiting for insulin signaling propagation in response to nelfinavir and the mechanism for defective PKB/Akt activation. Nelfinavir treatment of 3T3-L1 adipocytes impaired the insulin-stimulated translocation and membrane fusion of myc-glucose transporter (GLUT)-4-green fluorescent protein (GFP) reporter. Phosphorylation of PKB/Akt substrates including glycogen synthase kinase-3 and AS160 decreased in response to nelfinavir, and this remained true, even in cells with forced generation of phosphatidylinositol-3,4,5-trisphohphate (PIP3) by a membrane-targeted active PI 3-kinase, confirming that impaired PKB/Akt activation was rate limiting for insulin signal propagation. Cells expressing a GFP-tagged pleckstrin homology domain of general receptors for phosphoinositides 1, which binds PIP3, revealed intact PIP3-mediated plasma membrane translocation of this reporter in nelfinavir-treated cells. However, expression of a membrane-targeted catalytic subunit of PI 3-kinase failed to induce myc-GLUT4-GFP translocation in the absence of insulin, as it did in control cells. Conversely, a membrane-targeted and constitutively active PKB/Akt mutant was normally phosphorylated on S473 and T308, confirming intact PKB/Akt kinases activity, and induced myc-GLUT4-GFP translocation. Collectively, nelfinavir uncovers a postreceptor mechanism for insulin resistance, caused by interference with the sensing of PIP3 by PKB/Akt, leading to impaired GLUT4 translocation and membrane fusion.
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&NA;. "Nelfinavir + saquinavir resistance testing in HIV management". Inpharma Weekly &NA;, nr 1325 (luty 2002): 20. http://dx.doi.org/10.2165/00128413-200213250-00052.
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Petrich, Adam M., Violetta V. Leshchenko, Pei-Yu Kuo, B. Hilda Ye, Joseph A. Sparano i Samir Parekh. "Genomic and Pathway Connectivity Analyses Identify Novel Strategies to Overcome mTOR Inhibitor Resistance In DLBCL". Blood 116, nr 21 (19.11.2010): 436. http://dx.doi.org/10.1182/blood.v116.21.436.436.
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Abstract Abstract 436 mTOR inhibitors have been used with clinical success in solid tumors and non-Hodgkin lymphoma (NHL), and are attractive therapeutic options for DLBCL (diffuse large B-cell lymphoma, which has been shown to have constitutively active mTOR signaling). However, resistance to this class of agents remains problematic, and mechanisms of resistance are poorly understood. We performed candidate drug discovery using connectivity mapping and global gene expression profiling (GEP) to understand the pathways and genes responsible for resistance to the mTOR inhibitor Rapamycin (Sirolimus), which is the active metabolite of several clinically available mTOR inhibitors (eg, Temsirolimus, Everolimus). Treatment of DLBCL cell lines by Rapamycin at varying doses permitted stratification of cell lines into 2 groups of 3 cell lines each: sensitive (SU-DHL6, WSU-NHL, and Karpas-422) and resistant (SU-DHL4, OCI-Ly19, and Farage). Using the Affymetrix Human Gene 1.0 ST Array, we generated a profile of 1164 differentially-expressed genes (P<0.01) in the resistant cell lines. Pathway analysis of this particular gene expression signature enriched most strongly for the networks “EIF2 signaling” and “Regulation of eIF4 and p70S6K,” both of which are known to be involved in the PI3K and mTOR/AKT pathway. The genes thus identified present novel opportunities to understand and overcome resistance to mTOR inhibitors in DLBCL and other cancers. The Connectivity Map (CMAP) database contains a reference collection of more than 7,000 expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We next analyzed the differentially-expressed genes associated with mTOR inhibitor resistance with the CMAP database in order to identify compounds likely to reverse the profile associated with resistance. From over 6,000 agents, the top 2% (by connectivity score) contained two PI3K inhibitors (Wortmannin and LY-294002), the protease inhibitor Saquinavir, and multiple HDAC inhibitors (including both Vorinostat and Trichostatin-A in the top 40 drugs). Among protease inhibitors, Nelfinavir (and to a lesser extent Saquinavir), has been shown to have potent cytotoxicity in a variety of solid tumors, by inhibition of the AKT signaling pathway. To validate the hypothesis that modulation of AKT might help overcome mTOR inhibitor resistance, we targeted AKT with two agents: Nelfinavir and MK-2206. We found that Nelfinavir demonstrated significant cytotoxicity at clinically achievable levels in all DLBCL cell lines tested (including those resistant to Rapamycin), and inhibited phosphorylation of AKT and downstream proteins (including p70S6 kinase; S6 ribosomal protein; 4-EBP-1) in a dose-dependent fashion. Baseline total AKT and phosphorylated AKT levels correlated with degree of sensitivity to Nelfinavir. Inhibition of downstream mTOR signaling by Rapamycin synergized with Nelfinavir in cell kill and inhibition of cell cycle progression. MK-2206, an AKT inhibitor which has shown success in early-phase clinical trials, was evaluated in the same panel of cell lines and likewise demonstrated synergism with Rapamycin in cytotoxicity and cell cycle inhibition. The degree of synergism between Rapamycin and either Nelfinavir and MK-2206, as calculated using the Chou-Talalay equation, was comparable. We have also demonstrated synergy between Nelfinavir and doxorubicin, a key component in commonly utilized regimens for AIDS lymphoma patients such as CHOP (Cytoxan, Adriamycin, Oncovin and Prednisone). We are now validating these in vitro results in a mouse xenograft model of DLBCL. In conclusion, our study demonstrates that AKT inhibition by Nelfinavir results in potent cytotoxicity in DLBCL cell lines at clinically relevant doses. Our results may have implications for combination therapy beyond NHL in non-hematologic malignancies where mTOR inhibitors and MK-2206 are being used independently with clinical success. Furthermore, the synergistic combination of either Nelfinavir or MK-2206, along with Rapamycin, may permit use of lower doses of each drug to therapeutically inhibit mTOR/AKT signaling while potentially reducing toxicity from off-target effects from the individual drugs. Finally, the use of Nelfinavir has particular relevance in AIDS patients with DLBCL, where the drug has both anti-viral and anti-lymphoma potential. Disclosures: No relevant conflicts of interest to declare.
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Chow, W. A., S. Guo i F. Valdes-Albini. "HIV protease inhibitor (PI) therapy for liposarcoma". Journal of Clinical Oncology 24, nr 18_suppl (20.06.2006): 9564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9564.
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9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.
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Schmidt, Barbara, Klaus Korn, Brigitte Moschik, Christiane Paatz, Klaus Überla i Hauke Walter. "Low Level of Cross-Resistance to Amprenavir (141W94) in Samples from Patients Pretreated with Other Protease Inhibitors". Antimicrobial Agents and Chemotherapy 44, nr 11 (1.11.2000): 3213–16. http://dx.doi.org/10.1128/aac.44.11.3213-3216.2000.
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ABSTRACT The therapeutic success of an antiretroviral salvage regimen containing protease inhibitors (PI) is limited by PI-resistant viral strains exhibiting various degrees of resistance and cross-resistance. To evaluate the extent of cross-resistance to the new PI amprenavir, 155 samples from 132 human immunodeficiency virus type 1-infected patients were analyzed for viral genotype by direct sequencing of the protease gene. Concomitantly, drug sensitivity to indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir was analyzed by a recombinant virus assay. A total of 111 patients had been pretreated with 1-4 PI, but all were naive to amprenavir. A total of 105 samples (67.7%) were sensitive to amprenavir; 25 samples (16.1%) were intermediately resistant, and another 25 samples were highly resistant (4- to 8-fold- and >8-fold-reduced sensitivity, respectively). The mutations 46I/L, 54L/V, 84V, and 90M showed the strongest association with amprenavir resistance (P < 0.0001). The scoring system using 84V and/or any two of a number of mutations (10I/R/V/F, 46I/L, 54L/V, and 90M) predicted amprenavir resistance with a sensitivity of 86.0% and a specificity of 81.0% within the analyzed group of samples. Of 62 samples with resistance against 4 PI, 23 (37.1%) were still sensitive to amprenavir. In comparison, only 2 of 23 samples (8.7%) from nelfinavir-naive patients with resistance against indinavir, saquinavir, and ritonavir were still sensitive to nelfinavir. Amprenavir thus appears to be an interesting alternative for PI salvage therapy.
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Kolli, M., A. Ozen, N. Kurt-Yilmaz i C. A. Schiffer. "HIV-1 Protease-Substrate Coevolution in Nelfinavir Resistance". Journal of Virology 88, nr 13 (9.04.2014): 7145–54. http://dx.doi.org/10.1128/jvi.00266-14.
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Lisovsky, Irene. "Emergence of Nelfinavir and Lopinavir resistance relative to a clinically relevant human immunodeficiency virus type-1 single nucleotide polymorphism at position 36 in protease enzyme «in vitro»". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86996.
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The genetic differences and polymorphisms between HIV-1 subtype B and non-B subtypes have been well documented. Classically, however, antiretrovirals (ARVs), including protease inhibitors (PIs), have been designed based on structural and functional information obtained utilizing subtype B HIV-1. With the advent of antiretroviral therapy (ART) in developing countries and the emergence of non-B infections in developed countries, the impact of these polymorphisms must be evaluated in terms of ART efficacy.The 36th amino acid in the viral protease (PR) of B subtypes is Methionine (M), while non-B subtypes code for Isoleucine (I). I at position 36 is associated with PI resistance in subtype B HIV-1; therefore, we sought to investigate the effect of this single nucleotide polymorphism on emergence of resistance mutations and PI susceptibility in various HIV-1 subtypes in vitro. Our results indicate that the effect of this single nucleotide polymorphism appears to be subtype specific and PI specific.
Les différences génétiques (polymorphismes) entre les différents sous-types du VIH-1, soit B et non-B, sont bien documentées. Toutefois, les antirétroviraux incluant les inhibiteurs de la protéase, ont été conçus de façon structurelle et fonctionnelle en utilisant les informations obtenues à partir du sous-type B. L'impact des polymorphismes des différents sous-types du VIH-1 sur l'efficacité des antirétroviraux doit être évalué dû à l'émergence des infections de sous-types non-B dans les pays développés ainsi qu'avec l'arrivée de la thérapie antirétrovirale dans les pays en voie de développement.
Le 36e acide aminé de la protéase virale de sous-type B du VIH-1 est une méthionine. Cependant, cet acide aminé est remplacé par une isoleucine dans les sous-types non-B. La présence d'une isoleucine à la position 36 entraîne une résistance du VIH-1 sous-type B pour les inhibiteurs de la protéase. Nous avons examiné l'effet de ce polymorphisme sur les mutations de résistance dans les différents sous-types de VIH in vitro. Nos résultats indiquent que l'effet de ce polymorphisme serait différent selon le sous-type.
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GUPTA, ANKITA. "COMPUTATIONAL CHARACTERIZATION OF NON-ACTIVE SITE MUTATION V77I IN HIV-1 PROTEASE: POSSIBLE CONTRIBUTION TO NELFINAVIR RESISTANCE AND DEVELOPMENT OF NEW DRUG LEADS TARGETING HIV-1 PROTEASE". Thesis, 2016. http://dspace.dtu.ac.in:8080/jspui/handle/repository/16058.
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BACKGROUND
The Human immunodeficiency virus (HIV-1) protease is an attractive target for antiviral treatment and a number of therapeutically useful inhibitors have been designed against it. The emergence of drug resistant mutants of HIV-1 pose a serious problem for the conventional therapies been used so far. Here we have tried to study the effect of V77I mutation along with the co-occurring mutations L33F and K20T through multinanosecond molecular dynamics simulations. V77I is known to cause Nelfinavir (NFV) resistance in subtype B population of HIV-1 protease. We have reported the effect of this clinically relevant mutation on the binding of NFV and the conformational flexibility of the protease, and tried to generate derivates of potent drug Nelfinavir which can efficiently inhibit the wild and mutant proteases.
RESULT The study proposes that V77I-L33F mutant (DBM) showed greater flexibility and the flap separation was more with respect to the wild protease. The cavity size of stabilized DBM was also found to be increased which is responsible for the decreased interaction of Nelfinavir with all the cavity residues and hence decreased its binding affinity (Glide XP score: wild= -9.3, DBM= -7.8). On the other hand the binding affinity of V77I-L33F-K20T mutant (TPM) was found to be increased for Nelfinavir (Glide XP score= -10.3). The flap separation of TPM was less and the cavity size had also reduced with respect to wild protease.
CONCLUSION The resistant mutations had made DBM more stable in environment whereas the addition of third mutation K20T had made the protease TPM more susceptible to Nelfinavir. This lowered resistance can be the reason behind the less clinical relevance of TPM.
Części książek na temat "NELFINAVIR RESISTANCE"
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Raposo, L. M., M. B. Arruda, R. M. Brindeiro i F. F. Nobre. "Logistic Regression Models for Predicting Resistance to HIV Protease Inhibitor Nelfinavir". W IFMBE Proceedings, 1237–40. Cham: Springer International Publishing, 2014. http://dx.doi.org/10.1007/978-3-319-00846-2_306.
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Unissa, Ameeruddin Nusrath, i Luke Elizabeth Hanna. "Dissection of HIV-1 Protease Subtype B Inhibitors Resistance Through Molecular Modeling Approaches". W Big Data Analytics in HIV/AIDS Research, 149–70. IGI Global, 2018. http://dx.doi.org/10.4018/978-1-5225-3203-3.ch007.
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Protease (PR) is an important enzyme required for the posttranslational processing of the viral gene products of type-1 human immunodeficiency virus (HIV-1). Protease inhibitors (PI) act as competitive inhibitors that bind to the active site of PR. The I84V mutation contributes resistance to multiple PIs, and structurally, this mutation affects both sides of the enzyme active site. In order to get insights about this major resistance site to PR inhibitors using in silico approaches, in this chapter, the wild-type (WT) and mutant (MT) I84V of PR were modeled and docked with all PR inhibitors: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, and Tipranavir. Docking results revealed that in comparison to the WT, the binding score was higher for the MT-I84V. Thus, it can be suggested that the high affinity towards inhibitors in the MT could be due to the presence of energetically favorable interactions, which may lead to tight binding of inhibitors with the MT protein, leading to the development of PR resistance against PIs in HIV-1 eventually.
Streszczenia konferencji na temat "NELFINAVIR RESISTANCE"
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"Probabilistic Neural Network for Predicting Resistance to HIV-Protease Inhibitor Nelfinavir". W International Conference on Bioinformatics Models, Methods and Algorithms. SCITEPRESS - Science and and Technology Publications, 2014. http://dx.doi.org/10.5220/0004735900170023.
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Guan, Min. "Abstract 2653: Nelfinavir induces apoptosis in hormone-resistant prostate cancer cells through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6". W Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2653.
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