This July 2014 edition of the IAS-USA drug resistance mutations list updates the figures last published in March 2013. The following mutations have been added to existing classes or drugs: K65E/N has been added to the bars for the nucleoside and nucleotide analogue reverse transcriptase inhibitors (nRTIs) abacavir, didanosine, emtricitabine, lamivudine, stavudine, and tenofovir; L100I has been added to the bar for the nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) rilpivirine; and F121Y has been added to the bars for the integrase strand transfer inhibitors (InSTIs) dolutegravir, elvitegravir, and raltegravir. With regard to protease inhibitors (PIs), it cannot be excluded that drug resistance may be selected for outside the protease encoding region. 

2022 update of the drug resistance mutations in HIV-1.

https://digital.csic.es/bitstream/10261/228549/1/Men%c3%a9ndez-AriasL_Viral%20reverse%20transcriptases.pdf

Viral reverse transcriptases.

The nitrile group is an important functional group widely found in both pharmaceutical agents and natural products. More than 30 nitrile-containing pharmaceuticals have been approved by the FDA for the management of a broad range of clinical conditions in the last few decades. Incorporation of a nitrile group into lead compounds has gradually become a promising strategy in rational drug design as it can bring additional benefits including enhanced binding affinity to the target, improved pharmacokinetic profile of parent drugs, and reduced drug resistance. This paper reviews the existing drugs with a nitrile moiety that have been approved or in clinical trials, involving their targets, molecular mechanism of pharmacology and SAR studies, and classifies them into different categories based on their clinical usages.

Nitrile-containing pharmaceuticals: target, mechanism of action, and their SAR studies.

The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretrovirals, integrase (IN) strand transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of HIV intasomes bound to the latest generation INSTIs. These structures highlight how small changes in the IN active site can have significant implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.

/pdf/structural-basis-for-strand-transfer-inhibitor-binding-to-4scrq8ajye.pdf

Structural basis for strand-transfer inhibitor binding to HIV intasomes.

Approved HIV reverse transcriptase inhibitors in the past decade

Background Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 A from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new 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 2 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.

/pdf/rilpivirine-and-doravirine-have-complementary-efficacies-12cj7lzjnv.pdf

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

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 A from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs. Using a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs. The antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants.

/pdf/rilpivirine-analogs-potently-inhibit-drug-resistant-hiv-1-5dn1mjy3ea.pdf

Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants

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

Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants