Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles.
Abstract: However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment.
Abstract: The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased.
Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties.
PMID: 30624934
2019
Journal of medicinal chemistry
Conclusion: Especially, 13c2 and 13c4 proved to be the exceptionally potent inhibitors, exhibiting EC50 values of 0.9-7.0 nM against single NNRTI-resistant strains L100I, K103N, Y181C, Y188L, and E138K in MT-4 cells and bringing approximately 1.3- to 3.6 fold improvement in potency compared with ETV (EC50 = 3.3-20.4 nM).
Result: As noted above, 13c2 can inhibit single (L100I, K103N, Y181C, Y188L, E138K) and double (F227+V106A) mutated HIV-RT variants (see Figure S3 for the location of these mutations).
Result: In the case of
High predictive efficacy of integrase strand transfer inhibitors in perinatally HIV-1-infected African children in therapeutic failure of first- and second-line antiretroviral drug regimens recommended by the WHO.
PMID: 30891603
2019
The Journal of antimicrobial chemotherapy
Abstract: Two (2/18; 11.1%) viruses from children treated with a first-line regimen had INSTI DRMs at codon 138 (E138K and E138T), which is known to harbour major resistance mutations, and also had the accessory mutations L74I, G140K, G140R and G163R.
Result: In addition, the HIV-1 strain harbouring the E138K DRM also displayed accessory mutations G140K, G163R (Table 2) and APOBEC-related mutations not associated with resistance, including G82E, E85K, G106K, D116N, D167N
Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.
PMID: 30721060
2019
Journal of medicinal chemistry
Abstract: Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility.
Abstract: The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 muM, EC50(E138K) = 0.0075 muM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 >= 173 muM).
Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort.
Introduction: However, the landscape of antiretrovirals is changing continuously and new mutations such as E138A/G/K/Q/R (that confers resistance to the NNRTI rilpivirine (RPV), approved in 2011) are therefore not covered by this list.
Result: Mutations E138A/G/K/R were found in 99 of 186 viruses (52.9%) showing RPV resistance, which account for 40% of all NNRTI-resistant viruses.
Result: The NNRTI mutations at position E138 (
Result: The most common TDRMs found in baseline samples were the T215 revertants, followed by E138A/G/K/Q/R, K103NS, V179DE and M41L (S1 Table).
Development of the R263K Mutation to Dolutegravir in an HIV-1 Subtype D Virus Harboring 3 Class-Drug Resistance.
PMID: 30648124
2019
Open forum infectious diseases
Introduction: A number of additional mutations observed in patients can increase DTG resistance, including L74M and E138K.
High Levels of HIV-1 Drug Resistance in Children Who Acquired HIV Infection Through Mother to Child Transmission in the Era of Option B+, Haiti, 2013 to 2014.
PMID: 30640198
2019
The Pediatric infectious disease journal
Result: Twenty-nine (9.5%) of the children had additional NNRTI mutations (A98G, E138A/G/K/Q, H221Y, and M230L) that confer resistance to second generation NNRTI drugs etravirine and rilpivirine.
Discovery of potent HIV-1 non-nucleoside reverse transcriptase inhibitors by exploring the structure-activity relationship of solvent-exposed regions I.
PMID: 30381875
2019
Chemical biology & drug design
Abstract: Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1.
Virological outcomes of boosted protease inhibitor-based first-line ART in subjects harbouring thymidine analogue-associated mutations as the sole form of transmitted drug resistance.
PMID: 30544247
2019
The Journal of antimicrobial chemotherapy
Method: TDR mutations were defined according to the WHO 2009 surveillance list, with the addition of any unlisted change at position T215 and the non-polymorphic RT mutation E138K.
Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort.
Abstract: Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases.
Abstract: The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R.
HIV mutation literature information.
PMID: 
2020
ACS infectious diseases
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