Comprehending the Structure, Dynamics, and Mechanism of Action of Drug-Resistant HIV Protease

Dakshinamoorthy, Avinash; Asmita, Ananya; Senapati, Sanjib

doi:10.1021/acsomega.2c08279

Cited by 5 publications

(3 citation statements)

References 110 publications

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“…M46 is located near the edge of the binding pocket, close to the flap residues, but does not make any direct contact with GS-9770. Mutations at position M46 have been predicted to change the flexibility and dynamics of the flap ( 12 ). The L24I, I64V, and A77I substitutions were not present in any of the clinical isolates tested herein; however, L24I has been observed in PLWH receiving IDV and LPV therapy, whereas the I64V and A77I substitutions are non-polymorphic mutations often associated with resistance to PIs ( 13 ).…”

Section: Discussionmentioning

confidence: 99%

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

Mulato,

Lansdon,

Aoyama

et al. 2024

Antimicrob Agents Chemother

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Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

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Section: Discussionmentioning

confidence: 99%

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

Mulato,

Lansdon,

Aoyama

et al. 2024

Antimicrob Agents Chemother

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“…Although HIV-1 PR NPs only moderately impact enzyme activity and viral fitness, their presence has been shown to give rise to enhanced drug resistance [ 49 , 50 , 51 , 52 ]. Thus, by obtaining a better understanding of these alternate conformations as well as “hot spots” that can help induce a closed-like state, this work adds to a growing field of novel ways to target HIV-1 PR and drug resistance [ 38 , 48 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. These concepts are also being explored in drug development against other proteases in emerging diseases [ 66 , 67 , 68 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Polymorphisms D60E and I62V Stabilize a Closed Conformation in HIV-1 Protease in the Absence of an Inhibitor or Substrate

Tran,

Fanucci

2024

Viruses

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HIV infection remains a global health issue plagued by drug resistance and virological failure. Natural polymorphisms (NPs) contained within several African and Brazilian protease (PR) variants have been shown to induce a conformational landscape of more closed conformations compared to the sequence of subtype B prevalent in North America and Western Europe. Here we demonstrate through experimental pulsed EPR distance measurements and molecular dynamic (MD) simulations that the two common NPs D60E and I62V found within subtypes F and H can induce a closed conformation when introduced into HIV-1PR subtype B. Specifically, D60E alters the conformation in subtype B through the formation of a salt bridge with residue K43 contained within the nexus between the flap and hinge region of the HIV-1 PR fold. On the other hand, I62V modulates the packing of the hydrophobic cluster of the cantilever and fulcrum, also resulting in a more closed conformation.

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“…Typically, cART inhibits deterioration of HIV by preventing specific critical steps in the virus’s life cycle with multiple antiretroviral drugs, including protease inhibitors (PIs), integrase strand-transfer inhibitors (INSTIs), entry inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) ( De Clercq and Li, 2016 ). However, drug failure can result from insertion mutations, replacement mutations, high mutation rate-induced sequence variation in the capsid protein, and drug-induced modifications to HIV enzymes ( Tang and Shafer, 2012 ; Saito and Yamashita, 2021 ; Richetta et al, 2022 ; Dakshinamoorthy et al, 2023 ). As mutations accumulate, some viruses become resistant, eventually creating new subtypes.…”

Section: Introductionmentioning

confidence: 99%

Development and emerging trends of drug resistance mutations in HIV: a bibliometric analysis based on CiteSpace

Chen,

Lai

2024

Front. Microbiol.

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BackgroundAntiretroviral therapy has led to AIDS being a chronic disease. Nevertheless, the presence of constantly emerging drug resistance mutations poses a challenge to clinical treatment. A systematic analysis to summarize the advancements and uncharted territory of drug resistance mutations is urgently needed and may provide new clues for solving this problem.MethodsWe gathered 3,694 publications on drug resistance mutations from the Web of Science Core Collection with CiteSpace software and performed an analysis to visualize the results and predict future new directions and emerging trends. Betweenness centrality, count, and burst value were taken as standards.ResultsThe number of papers on HIV medication resistance mutations during the last 10 years shows a wave-like trend. In terms of nation, organization, and author, the United States (1449), University of London (193), and Mark A. Wainberg (66) are the most significant contributors. The most frequently cited article is “Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.” Hot topics in this field include “next-generation sequencing,” “tenofovir alafenamide,” “children,” “regimens,” “accumulation,” “dolutegravir,” “rilpivirine,” “sex,” “pretreatment drug resistance,” and “open label.” Research on drug resistance in teenagers, novel mutation detection techniques, and drug development is ongoing, and numerous publications have indicated the presence of mutations related to current medications. Therefore, testing must be performed regularly for patients who have used medications for a long period. Additionally, by choosing medications with a longer half-life, patients can take fewer doses of their prescription, increasing patient compliance.ConclusionThis study involved a bibliometric visualization analysis of the literature on drug resistance mutations, providing insight into the field’s evolution and emerging patterns and offering academics a resource to better understand HIV drug resistance mutations and contribute to the field’s advancement.

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Comprehending the Structure, Dynamics, and Mechanism of Action of Drug-Resistant HIV Protease

Cited by 5 publications

References 110 publications

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability

Natural Polymorphisms D60E and I62V Stabilize a Closed Conformation in HIV-1 Protease in the Absence of an Inhibitor or Substrate

Development and emerging trends of drug resistance mutations in HIV: a bibliometric analysis based on CiteSpace

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