Lai, Ming-Tain; Feng, Meizhen; Xu, Min; Ngo, Winnie; Diamond, Tracy L.; Hwang, Carey; Grobler, Jay A.; Hazuda, Daria J.; Asante-Appiah, Ernest published the artcile< Doravirine and islatravir have complementary resistance profiles and create a combination with a high barrier to resistance>, COA of Formula: C19H34O2, the main research area is doravirine islatravir combination complementary resistance profile; HIV-1; NNRTI; NRTTI; RT; doravirine; human immunodeficiency virus; islatravir; reverse transcriptase.
Doravirine (DOR), a non-nucleoside reverse transcriptase inhibitor (NNRTI), was approved for treatment of HIV-1 infection in 2018. In the pivotal phase 3 trials, DRIVE-FORWARD and DRIVE-AHEAD, 7 out of 747 (0.9%) treatment-naive participants treated with DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) met protocol-defined virol. failure criteria and showed phenotypic resistance to DOR at week 48. The most common DOR resistance-associated mutation (RAM) detected in 5 of the 7 resistant isolates was F227C. Six isolates bearing NRTI RAMs (M184V and/or K65R) were resistant to lamivudine (3TC) and emtricitabine (FTC) but not to other approved NRTIs. All DOR-resistant isolates were susceptible or hypersusceptible (fold change of <0.25) to islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Isolate hypersusceptibility to ISL required F227C, in contrast to zidovudine, an NRTI, which required M184V. Based on the frequent emergence of F227C, we hypothesized that DOR and ISL would create a combination (DOR/ISL) with a high barrier to resistance. In de novo resistance selection studies in MT4-GFP cells (MT4 cells engineered to express green fluorescent protein), DOR/ISL synergistically prevented viral breakthrough at a threshold of 2x the half-maximal inhibitory concentration (IC50). DOR/ISL exhibited a higher barrier to resistance than DOR/3TC and dolutegravir (DTG)/3TC. Resistance anal. showed no emergence of substitutions at F227, an observation consistent with its ability to confer hypersusceptibility to ISL. Overall, the data demonstrate that DOR/ISL creates a 2-drug combination with a higher barrier to resistance, consistent with the reported clin. activity. Antimicrobial Agents and Chemotherapy published new progress about Antiviral agents. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, COA of Formula: C19H34O2.
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