Review of Doravirine Resistance Patterns Identified in Participants During Clinical Development.
PMID: 32925358
2020
Journal of acquired immune deficiency syndromes (1999)
Abstract: DOR was rationally designed to address limitations associated with other approved NNRTIs, particularly resistance from common NNRTI resistance-associated mutants containing K103N, Y181C, or G190A reverse transcriptase substitutions.
Introduction: D
Method: None of these participants had RT K103N, Y181C, or G190A substitutions at baseline.
Method: Overall, 4% (n = 24/656) of participants entered the trial with RT K103N, Y181C, and/or G190A substitutions.
New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains.
PMID: 32883642
2020
European journal of medicinal chemistry
Abstract: Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N-Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs.
Abstract: Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results.
Abstract: Kinetic experiments disclosed that derivative 12 preferentially binds WT and
Structural investigation of 2-naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site.
Abstract: Additional modifications to these compounds at the 4-position, computationally designed to compensate for the Y181C mutation, do not demonstrate improved potency.
Abstract: Comparison of 2-naphthyl phenyl ethers bound to Y181C RT reveal that compounds that interact with the invariant W229 are more capable of retaining efficacy against the resistance mutation.
Abstract: Further biochemical and structural work demonstrated differences in potency against the Y181C mutation and binding mode of the compounds.
Abstract: One class of developed compounds are the 2-naphthyl phenyl ethers, showing promising efficacy against the Y181C RT mutation.
Targeting HIV-1 RNase H: N'-(2-Hydroxy-benzylidene)-3,4,5-Trihydroxybenzoylhydrazone as Selective Inhibitor Active against NNRTIs-Resistant Variants.
Abstract: Here, we characterize the mode of action of N'-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 microM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus.
Result: Antiviral activity and cytotoxicity of compounds 13 and 21 were determined at 5 days on MT4 cells against HIV-1 NL4.3 wt strain and HIV-1 NL4.3 carrying the K103N-Y181C double mutation, commonly selected in patients and that confers resistance to non-nucleoside RT inhibitors (NNRTIs).
Result: Both N-acylhydrazone derivatives inhibited viral replication retaining similar potency of inhibition against the PMID: 32642769
2020
The Journal of antimicrobial chemotherapy
Abstract: The four virological failures were due to three ART interruptions and one incomplete adherence (selection of Y181C RAM).
Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7.
Abstract: In addition, it showed moderate inhibitory potency (EC50 = 1.329 muM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells).
Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors.
PMID: 32712537
2020
European journal of medicinal chemistry
Abstract: Among all the chiral derivatives, (S)-(-)-12a showed the best potency with the antiviral activities against wild-type (WT) and single mutant strains (L100I, K103 N, Y181C, E138K; especially Y188L), and RT enzyme in the low nanomolar concentration range.
Prevalence and characteristics of HIV drug resistance among antiretroviral treatment (ART) experienced adolescents and young adults living with HIV in Ndola, Zambia.
Abstract: Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing.
Abstract: There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine.
Discussion: The high prevalence of the Y181C and Y188C mutations has been demonstrated in earlier studies from the region including Zambia.
Discussion: The third major finding of this study was the high prevalence of the Y188CE (36.2%) and
HIV mutation literature information.
PMID: 
2020
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