<i>In Vitro</i>
            Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

Feng, Meizhen; Wang, Deping; Grobler, Jay A.; Hazuda, Daria J.; Miller, Michael D.; Lai, Ming‐Tain

doi:10.1128/aac.04201-14

Cited by 94 publications

(90 citation statements)

References 27 publications

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“…PCR products were genotyped using an automated population-based fulllength sequencing method. The primers used for PCR amplification were the same as those described previously (12).…”

Section: Methodsmentioning

confidence: 99%

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Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Feng

Sachs

et al. 2016

Antimicrob Agents Chemother

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Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC 50 s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC 50 for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting.T he introduction of highly active antiretroviral therapy (HAART) in 1996 has significantly reduced the morbidity and mortality associated with HIV-1 infection (1, 2). However, the clinical and immunologic benefits of antiretroviral therapy can be compromised by the emergence of drug-resistant viruses due to suboptimal treatment or adherence.Drug-resistant mutants can be transmitted to an uninfected individual. Transmitted drug-resistant (TDR) mutants limit the choice of first-line combination antiretroviral therapy, decrease the efficacy of subsequent antiretroviral regimens, and increase the risk of treatment failure (3-5). TDR mutants have been documented among treatment-naive patients, with prevalences ranging from 3% to 24%, depending on the cohort and geographic characteristics (6). Importantly, transmitted nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants are of particular concern, as they have the ability to persist for years after initial infection, suggesting the low impact of NNRTI-resistant mutations on viral fitness (7-9). The persistence of NNRTI-associated mutants after the discontinuation of an NNRTI-containing regimen may contribute to the prevalence of NNRTI-associated TDR mutants.Three mutants, K103N, Y181C, and G190A, account for Ͼ90% of the NNRTI-associated TDR mutants in the United States (10). K103N, Y181C, and K103N/Y181...

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“…PCR products were genotyped using an automated population-based fulllength sequencing method. The primers used for PCR amplification were the same as those described previously (12).…”

Section: Methodsmentioning

confidence: 99%

“…A new NNRTI capable of suppressing the most prevalent NNRTI-associated and TDR mutants would therefore be a significant addition to current HIV-1 therapeutic options. Doravirine (DOR, formerly MK-1439) is a novel NNRTI that displays excellent antiviral activity against these most prevalent NNRTI-associated mutants in vitro (12).…”

mentioning

confidence: 99%

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Feng

Sachs

et al. 2016

Antimicrob Agents Chemother

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“…Fig. 1) is being developed by Merck and is currently in Phase III clinical trials [16, 17]. DOR can effectively inhibit the replication of viruses that carry several prevalent NNRTI-resistance mutations; however, DOR selected mutations in RT that confer reduced susceptibility in experiments done in cultured cells.…”

Section: Introductionmentioning

confidence: 99%

“…DOR can effectively inhibit the replication of viruses that carry several prevalent NNRTI-resistance mutations; however, DOR selected mutations in RT that confer reduced susceptibility in experiments done in cultured cells. Mutations that reduced the susceptibility of RT to DOR did not, in general, confer a decrease in susceptibility to RPV and vice-versa, suggesting this difference would make DOR a useful new drug [17]. However, in this initial study, only a limited number of mutants were tested.…”

Section: Introductionmentioning

confidence: 99%

Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants

Smith

Pauly

Akram

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be FDA-approved to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 Å from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of WT HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new a NNRTI in phase III clinical trials. Methods Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT. Results Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these two NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI resistance mutations. Conclusions This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities.

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“…Results from the assay reveal that our leading catechol diether compounds maintain potency for RT K101P variants, while rilpivirine resistance is reaffirmed as in earlier reported studies. 5,10,15,17,26 In order to understand the effects of the K101P mutation, kinetic data for the RT (K101P) enzyme was evaluated and compared to the wild-type, RT (WT). We also obtained a cocrystal structure of RT (K101P) with a catechol diether, compound 3, to evaluate the binding interactions in the nonnucleoside pocket.…”

mentioning

confidence: 99%

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

Gray

Frey

Laskey

et al. 2015

ACS Med. Chem. Lett.

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Catechol diether compounds have nanomolar antiviral and enzymatic activity against HIV with reverse transcriptase (RT) variants containing K101P, a mutation that confers high-level resistance to FDA-approved non-nucleoside inhibitors efavirenz and rilpivirine. Kinetic data suggests that RT (K101P) variants are as catalytically fit as wild-type and thus can potentially increase in the viral population as more antiviral regimens include efavirenz or rilpivirine. Comparison of wild-type structures and a new crystal structure of RT (K101P) in complex with a leading compound confirms that the K101P mutation is not a liability for the catechol diethers while suggesting that key interactions are lost with efavirenz and rilpivirine.

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In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development Pathways

Cited by 94 publications

References 27 publications

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

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