Abstract: A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H.
Structural basis of second-generation HIV integrase inhibitor action and viral resistance.
Abstract: Glutamine-148 histidine (Q148H) and glycine-140 serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site.
Abstract: The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations.
Introduction: An exception is Thr138: in HIV-1, E138T potentiates resistance of Q148H-containing viruses.
Introduction: As a start, we analyzed respective side chains in our SIVrcm PMID: 32041622
2020
AIDS research and therapy
Abstract: The Y143R/H/C substitutions were the most prevalent, followed by the N155H, and both Q148H/K and G140S/A in the same proportion.
Table: Discussion: On the other hand, we do not find a significant difference between the mean viral load of the subjects with DTG resistance compared to the subjects without DTG resistance (n = 22), nor with samples harbouring a G140S/A + Q148H/R/K combination (n = 3) as described in that study.
Discussion: This is important since the presence of the G140S mutation in combination with the Q148H mutation has been described to improve the viral fitness and increase the viral load in RAL-resistant subjects.
High prevalence of integrase mutation L74I in West African HIV-1 subtypes prior to integrase inhibitor treatment.
PMID: 32105319
2020
The Journal of antimicrobial chemotherapy
Introduction: A recent report suggested that methionine at residue 74 was in closer proximity to T97 and F121 as compared with leucine at position 74 in a modelled subtype C integrase and, of note, L74F was found to contribute to high-level dolutegravir resistance when combined with major mutations G140S and Q148H.
Characterization of HIV-1 Integrase Gene and Resistance Associated Mutations Prior to Roll out of Integrase Inhibitors by Kenyan National HIV-Treatment Program in Kenya.
PMID: 32116431
2020
Ethiopian journal of health sciences
Result: From analysis of these integrase sequences, no primary mutations (Y143R=C=H, Q148H=R=K, and N155H=S) associated with reduced susceptibility to the integrase inhibitors Raltegravir and Elvitegravir were detected.
Occurrence of the S230R integrase strand inhibitor mutation in a treatment-naive individual case report.
Discussion: Common INSTI RAMS include R263K, Q148H/R/K, G118R, G140A/S/C, E138A/K/T, N155H, and Y143C/R.
Evidence for Disruption of Mg(2+) Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors.
PMID: 32974383
2020
Frontiers in molecular biosciences
Introduction: Here, we use information from the cryo-EM STC structure of the HIV-1 IN to build models of cSSC of the wild-type (WT) IN, the N155H variant, and the double mutant N155H+Q148H.
Introduction: The simulations were used to better understand the resistance mechanisms of N155H, as well as the reasons why N155H and Q148H are mutually exclusive.
Introduction: There are three commonly frequent resistance pathways among the resistance mutations: N155H, Q148HRK, and Y143HC; interestingly, N155H and Q14
Virologic suppression in patients with a documented M184V/I mutation based on the number of active agents in the antiretroviral regimen.
Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains.
PMID: 32125378
2020
The Journal of antimicrobial chemotherapy
Abstract: INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively).
Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C Integrase-Dolutegravir binding.
Introduction: Genetic resistance pathways including primary mutations at codons Y143C/H/R, Q148H/K/R or N155H together with one or more additional associated secondary mutations at L74M, E92Q, T97A, E138E/A/K or G140S/A, has b
Discussion: showed the structural impact of mutations Q148H/R and G140S/A on the flexibility of the HIV-1 IN as a mechanism for RAL resistance.
Discussion: study with the WT showing higher pair interaction energy compared to the G140S/Q148H double mutant.
HIV mutation literature information.
PMID: 
2020
Bioorganic & medicinal chemistry letters
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