Mechanistic Study of Common Non-Nucleoside Reverse Transcriptase Inhibitor-Resistant Mutations with K103N and Y181C Substitutions

Lai, Ming‐Tain; Munshi, Vandna; Lu, Meiqing; Feng, Meizhen; Hrin-Solt, Renee; McKenna, Philip M.; Hazuda, Daria J.; Miller, Michael D.

doi:10.3390/v8100263

Cited by 17 publications

(14 citation statements)

References 28 publications

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“…Our data revealed that all of the substitutions at position Y181 (i.e., Y181C, Y181I, Y181V, and Y181F) decreased the catalytic efficiency (k pol /K d ) of RT and that these decreases were driven by both changes in K d and k pol (maximum rate of dNTP incorporation). This finding is consistent with prior reports that Y181C, Y181I, Y181V, and Y181F decrease the replicative capacity of HIV-1 (14,15). NVP, EFV, and RPV binding exerted profound effects on both nucleotide affinity and the rate of nucleotide incorporation for both the WT and mutant RT-T/P complexes (Table 4).…”

Section: Nucleotide Incorporation Reactions Carried Out By Wt and Mutsupporting

confidence: 92%

Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase

Barnard

Huber

Sluis‐Cremer

2019

Antimicrob Agents Chemother

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Substitutions at residue Y181 in HIV-1 reverse transcriptase (RT), in particular, Y181C, Y181I, and Y181V, are associated with nonnucleoside RT inhibitor (NNRTI) cross-resistance. In this study, we used kinetic and thermodynamic approaches, in addition to molecular modeling, to gain insight into the mechanisms by which these substitutions confer resistance to nevirapine (NVP), efavirenz (EFV), and rilpivirine (RPV). Using pre-steady-state kinetics, we found that the dissociation constant (K d ) values for inhibitor binding to the Y181C and Y181I RT-template/primer (T/P) complexes were significantly reduced. In the presence of saturating concentrations of inhibitor, the Y181C RT-T/P complex incorporated the next correct deoxynucleoside triphosphate (dNTP) more efficiently than the wild-type (WT) complex, and this phenotype correlated with decreased mobility of the RT on the T/P substrate. Interestingly, we found that the Y181F substitution in RT-which represents a transitional mutation between Y181 and Y181I/V, or a partial revertant-conferred hypersusceptibility to EFV and RPV at both the virus and enzyme levels. EFV and RPV bound more tightly to Y181F RT-T/P. Furthermore, inhibitor-bound Y181F RT-T/P was less efficient than the WT complex in incorporating the next correct dNTP, and this could be attributed to increased mobility of Y181F RT on the T/P substrate. Collectively, our data highlight the key role that Y181 in RT plays in NNRTI binding.

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Section: Nucleotide Incorporation Reactions Carried Out By Wt and Mutsupporting

confidence: 92%

Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase

Barnard

Huber

Sluis‐Cremer

2019

Antimicrob Agents Chemother

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“…Combinations of these mutations lead to a significant decrease in susceptibility to the inhibitor. Several particular mechanisms related to resistance to NNRTIs are described in publications [ 37 , 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…A probable mechanism leading to the resistance to RT in position Y181C and Y188L/C/H/F is associated with the loss of π - π stacking between the changed amino acids residues and small molecules [ 44 ]. The loss of antiretroviral activity in K103N mutants can be associated with several different mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review

2018

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Currently, millions of people are living with human immunodeficiency virus type 1 (HIV-1), which causes acquired immunodeficiency syndrome. However, the spread of the HIV-1 resistance to antiviral agents is the major problem in the antiretroviral therapy and medical management of HIV-infected patients. HIV-1 reverse transcriptase (RT) is one of the key viral targets for HIV-1 inhibition. Therefore, the studies on the combatting the HIV resistance that occurs due to the structural changes in RT, are in great demand. This work aims to provide an overview of the state-of-the-art molecular docking approaches applied to the studies of the HIV-1 resistance, associated with RT structure changes. We have reviewed recent studies using molecular docking with mutant forms of RT. The work discusses the modifications of molecular docking, which have been developed to find the novel molecules active against resistance mutants of RT and/or recombinant strains of HIV-1. The perspectives of the existing algorithms of molecular docking to the studies on molecular mechanisms of resistance and selection of the correct binding poses for the reverse transcriptase inhibitors are discussed.

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“…As to the K103N mutation, it was long believed that it prevented the entry of NNRTIs by stabilizing the closed conformation of NNIBP ( Hsiou et al, 2001 ). However, a more recent study indicates that the resistance is more likely caused by the electrostatic difference between Asn103 and Lys103 ( Lai et al, 2016 ). In the light of this new piece of data, the K103N mutation seems to utilize the same mechanism as Y181C and Y188L do to confer resistance to NNRTIs: by altering the shape or surface property of the NNIBP.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors

Yang

Kang

Nguyen

et al. 2018

eLife

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Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.

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Mechanistic Study of Common Non-Nucleoside Reverse Transcriptase Inhibitor-Resistant Mutations with K103N and Y181C Substitutions

Cited by 17 publications

References 28 publications

Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase

Nonnucleoside Reverse Transcriptase Inhibitor Hypersusceptibility and Resistance by Mutation of Residue 181 in HIV-1 Reverse Transcriptase

Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review

Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors

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