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The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

ABSTRACT: Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol-thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.

SUBMITTER: Nikolayevskiy H

PROVIDER: S-EPMC8132308 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

Nikolayevskiy Herman H Robello Marco M Scerba Michael T MT Pasternak Evan H EH Saha Mrinmoy M Hartman Tracy L TL Buchholz Caitlin A CA Buckheit Robert W RW Durell Stewart R SR Appella Daniel H DH

European journal of medicinal chemistry 20190609

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenz ...[more]

PMID: 31252286

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Project description:To explore reasons for the disproportionate metabolic and cardiovascular disease burdens among older HIV-infected persons, we investigated whether associations of CD4 count and HIV viral load (VL) with non-high-density lipoprotein cholesterol (non-HDL-C) and high-density lipoprotein cholesterol [HDL-C] differed by age. Longitudinal clinical and laboratory data were collected between 2011 and 2016 for HIV-infected outpatients in the DC Cohort study. Using data for patients aged ≥21 years with ≥1 cholesterol result and contemporaneous CD4/VL results, we created multivariable linear regression models with generalized estimating equations. Among 3,912 patients, the median age was 50 years, 78% were male, 76% were non-Hispanic black, 93% were using antiretroviral therapy, 8% had a CD4 count <200 cells/μL, and 18% had an HIV VL ≥200 copies/mL. Overall, CD4 count <200 (vs. >500) cells/μL and VL ≥200 copies/mL were associated with lower non-HDL-C concentrations (p < .01), but associations were more positive with increasing age (CD4-age/VL-age interactions, p < .01). CD4 count <200 cells/μL was associated with lower non-HDL-C among patients aged <50 years [β = -7.8 mg/dL (95% confidence interval, CI: -13.2 to -2.4)] but higher non-HDL-C among patients aged 60-69 years [β = +8.1 mg/dL (95% CI: 0.02-16.2)]. VL ≥200 copies/mL was associated with lower non-HDL-C among patients aged <50 years [β = -3.3 mg/dL (95% CI: -6.7 to 0.1)] but higher non-HDL-C among patients aged ≥70 years [β = +16.0 mg/dL (95% CI: -1.4 to 33.3)], although precision was reduced in age-stratified analyses. Although no age differences were detected for HDL-C, VL ≥200 copies/mL was more strongly associated with lower HDL-C concentrations when CD4 count was <200 cells/μL [β = -7.0 mg/dL (95% CI: -9.7 to -4.3)] versus 200-500 cells/μL [β = -4.2 (95% CI: -5.9 to -2.6)] or >500 cells/μL [β = -2.2 (95% CI: -3.7 to -0.8)] (CD4-VL interaction, p < .01). We detected a novel age-modified relationship between immunosuppression and viremia and atherogenic cholesterol patterns. These findings may contribute to our understanding of the high risk of dyslipidemia observed among persons aging with HIV.

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The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

Publications

The structure-activity profile of mercaptobenzamides' anti-HIV activity suggests that thermodynamics of metabolism is more important than binding affinity to the target.

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