An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit

The ongoing development of drug resistance in HIV continues to push for the need of alternative drug targets in inhibiting HIV. One such target is the Reverse transcriptase (RT) enzyme which is unique and critical in the viral life cycle—a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical scaffolds from the National Cancer Institute (NCI) Diversity Set V that inhibited HIV-1 RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183, which has no known association with previously reported drug resistance. This finding supports the possibility of a novel druggable site on p51 for a new class of non-nucleoside RT inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally to only be in the micromolar range, the scaffolds serve as a proof-of-concept of targeting the HIV RT p51 subunit, with the possibility of medical chemistry methods being applied to improve inhibitory activity towards more effective drugs.

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An alternative HIV-1 non-nucleoside Reverse Transcriptase inhibition mechanism: Targeting the p51 subunit

10.1101/699470 ◽

2019 ◽

Cited By ~ 2

Author(s):

Kwok-Fong Chan ◽

Chinh Tran-To Su ◽

Alexander Krah ◽

Ser-Xian Phua ◽

Peter J. Bond ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Inhibitory Activity ◽

Drug Targets ◽

Experimental Testing ◽

Inhibition Mechanism ◽

New Class ◽

Alternative Drug ◽

Rt Inhibitors ◽

Hiv 1

AbstractHIV drug resistance continues to demand for alternative drug targets. Since Reverse Transcriptase (RT) is unique and critical for the virus life cycle, it is a rational target that is likely to have less off-target effects in humans. Serendipitously, we found two chemical compound scaffolds from the NCI Diversity Set V that inhibited the HIV1- RT catalytic activity. Computational structural analyses and subsequent experimental testing demonstrated that one of the two chemical scaffolds binds to a novel location in the HIV-1 RT p51 subunit, interacting with residue Y183 that has no known association with previously reported drug resistance. This finding leads to the notion of a novel druggable site on p51 for a new class of non-nucleoside RT Inhibitors that may inhibit HIV-1 RT allosterically. Although inhibitory activity was shown experimentally only to be in the hundreds micromolar range, the scaffolds serve as a proof-of-concept of targeting HIV RT p51, with the possibility for medical chemistry methods to be applied to improve the inhibitory activity, towards a functioning drug.

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HIV-1 Reverse Transcriptase (RT) Polymorphism 172K Suppresses the Effect of Clinically Relevant Drug Resistance Mutations to Both Nucleoside and Non-nucleoside RT Inhibitors

Journal of Biological Chemistry ◽

10.1074/jbc.m112.351551 ◽

2012 ◽

Vol 287 (35) ◽

pp. 29988-29999 ◽

Cited By ~ 7

Author(s):

Atsuko Hachiya ◽

Bruno Marchand ◽

Karen A. Kirby ◽

Eleftherios Michailidis ◽

Xiongying Tu ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Rt Inhibitors ◽

Hiv 1

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A Rough Set-Based Model of HIV-1 Reverse Transcriptase Resistome

Bioinformatics and Biology Insights ◽

10.4137/bbi.s3382 ◽

2009 ◽

Vol 3 ◽

pp. BBI.S3382 ◽

Cited By ~ 16

Author(s):

Marcin Kierczak ◽

Krzysztof Ginalski ◽

Michał Dramiñski ◽

Jacek Koronacki ◽

Witold Rudnicki ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Rough Set ◽

Molecular Mechanisms ◽

3D Structure ◽

Feature Selection Method ◽

Resistance Mutations ◽

Monte Carlo Feature Selection ◽

Rt Inhibitors ◽

Hiv 1

Reverse transcriptase (RT) is a viral enzyme crucial for HIV-1 replication. Currently, 12 drugs are targeted against the RT. The low fidelity of the RT-mediated transcription leads to the quick accumulation of drug-resistance mutations. The sequence-resistance relationship remains only partially understood. Using publicly available data collected from over 15 years of HIV proteome research, we have created a general and predictive rule-based model of HIV-1 resistance to eight RT inhibitors. Our rough set-based model considers changes in the physicochemical properties of a mutated sequence as compared to the wild-type strain. Thanks to the application of the Monte Carlo feature selection method, the model takes into account only the properties that significantly contribute to the resistance phenomenon. The obtained results show that drug-resistance is determined in more complex way than believed. We confirmed the importance of many resistance-associated sites, found some sites to be less relevant than formerly postulated and—more importantly—identified several previously neglected sites as potentially relevant. By mapping some of the newly discovered sites on the 3D structure of the RT, we were able to suggest possible molecular-mechanisms of drug-resistance. Importantly, our model has the ability to generalize predictions to the previously unseen cases. The study is an example of how computational biology methods can increase our understanding of the HIV-1 resistome.

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Characterization of HIV-1 reverse transcriptase drug resistance connection subdomain mutation N348I

10.32469/10355/14917 ◽

2011 ◽

Author(s):

Matthew M. Schuckmann

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Hiv 1

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Genetic Diversity and Drug Resistance of HIV-1 CRF55_01B in Guangdong, China

Current HIV Research ◽

10.2174/1570162x18666200415140652 ◽

2020 ◽

Vol 18 (3) ◽

pp. 210-218

Author(s):

Guolong Yu ◽

Yan Li ◽

Xuhe Huang ◽

Pingping Zhou ◽

Jin Yan ◽

...

Keyword(s):

Genetic Diversity ◽

Drug Resistance ◽

Reverse Transcriptase ◽

Phylogenetic Analyses ◽

Resistance Mutations ◽

Protease Inhibition ◽

Subtype B ◽

Primary Drug Resistance ◽

Hiv 1 ◽

Primary Drug

Background: HIV-1 CRF55_01B was first reported in 2013. At present, no report is available regarding this new clade’s polymorphisms in its functionally critical regions protease and reverse transcriptase. Objective: To identify the diversity difference in protease and reverse transcriptase between CRF55_01B and its parental clades CRF01_AE and subtype B; and to investigate CRF55_01B’s drug resistance mutations associated with the protease inhibition and reverse transcriptase inhibition. Methods: HIV-1 RNA was extracted from plasma derived from a MSM population. The reverse transcription and nested PCR amplification were performed following our in-house PCR procedure. Genotyping and drug resistant-associated mutations and polymorphisms were identified based on polygenetic analyses and the usage of the HIV Drug Resistance Database, respectively. Results: A total of 9.24 % of the identified CRF55_01B sequences bear the primary drug resistance. CRF55_01B contains polymorphisms I13I/V, G16E and E35D that differ from those in CRF01_AE. Among the 11 polymorphisms in the RT region, seven were statistically different from CRF01_AE’s. Another three polymorphisms, R211K (98.3%), F214L (98.3%), and V245A/E (98.3 %.), were identified in the RT region and they all were statistically different with that of the subtype B. The V179E/D mutation, responsible for 100% potential low-level drug resistance, was found in all CRF55_01B sequences. Lastly, the phylogenetic analyses demonstrated 18 distinct clusters that account for 35% of the samples. Conclusions: CRF55_01B’s pol has different genetic diversity comparing to its counterpart in CRF55_01B’s parental clades. CRF55_01B has a high primary drug resistance presence and the V179E/D mutation may confer more vulnerability to drug resistance.

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A Novel Ribonuclease with HIV-1 Reverse Transcriptase Inhibitory Activity from the Edible Mushroom Hygrophorus russula

Applied Biochemistry and Biotechnology ◽

10.1007/s12010-013-0180-8 ◽

2013 ◽

Vol 170 (1) ◽

pp. 219-230 ◽

Cited By ~ 9

Author(s):

Mengjuan Zhu ◽

Lijing Xu ◽

Xiao Chen ◽

Zengqiang Ma ◽

Hexiang Wang ◽

...

Keyword(s):

Reverse Transcriptase ◽

Inhibitory Activity ◽

Edible Mushroom ◽

Hiv 1

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Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00127-06 ◽

2006 ◽

Vol 50 (8) ◽

pp. 2772-2781 ◽

Cited By ~ 39

Author(s):

Zhijun Zhang ◽

Michelle Walker ◽

Wen Xu ◽

Jae Hoon Shim ◽

Jean-Luc Girardet ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immunodeficiency Virus ◽

Nonnucleoside Inhibitors ◽

Rt Inhibitors ◽

Hiv 1 ◽

M184v Mutation

ABSTRACT Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

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