2. Academic Validation
  3. Building Metabolically Stable and Potent Anti-HIV Thioether-Lipid Analogues of Tenofovir Exalidex: A thorough Pharmacological Analysis

Building Metabolically Stable and Potent Anti-HIV Thioether-Lipid Analogues of Tenofovir Exalidex: A thorough Pharmacological Analysis

  • J Med Chem. 2024 Oct 24;67(20):18204-18220. doi: 10.1021/acs.jmedchem.4c01510.
Michael P D'Erasmo 1,  Savita K Sharma 1,  Nicole Pribut 1,  Adriaan Basson 2,  Madhuri Dasari 1,  Perry Bartsch 1,  Sabrina E Iskandar 1,  Kyle E Giesler 1,  Samantha Burton 1,  Cindy A Derdeyn 3,  Dennis C Liotta 1,  Eric J Miller 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Emory University College of Arts & Sciences, Atlanta, Georgia 30322, United States.
  • 2 HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg 2000, Gauteng, South Africa.
  • 3 Department of Laboratory Medicine & Pathology, University of Washington School of Medicine, Seattle, Washington 98195, United States.
  • 4 Department of Pharmacology & Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
PMID: 39411803 DOI: 10.1021/acs.jmedchem.4c01510
Abstract

Inherently limited by poor bioavailability, Antiviral agent tenofovir (TFV) is administered to people living with HIV in prodrug form. However, current prodrugs are prematurely metabolized, compromising access to HIV-infected cells and inducing toxicity. Inspired by lipid conjugate TFV exalidex (TXL), we recently disclosed TXL analogs with potent activity and robust hepatic stability in vitro, as well as attractive oral PK profiles in vivo. In parallel, we discovered the equipotent and equally stable hexadecylthiopropyl (HTP) derivative of TXL (2a). Reported herein are the synthetic and bioanalytic efforts that led to potent, safe, and hepatically stable HTP derivatives. While HTP analog 16h showed the most attractive PK profile in mice (55% F) discrepancies in translating in vitro cell-based results to in vivo PK data, for certain prodrugs, indicated that further in vitro/in vivo optimization is required for continued advancement of this program.

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