2. Academic Validation
  3. Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1

  • Sci Transl Med. 2023 Feb 22;15(684):eabn2038. doi: 10.1126/scitranslmed.abn2038.
Carl J Balibar 1,  Daniel J Klein 2,  Beata Zamlynny 2,  Tracy L Diamond 1,  Zhiyu Fang 1,  Carol A Cheney 1,  Jan Kristoff 1,  Meiqing Lu 1,  Marina Bukhtiyarova 3,  Yangsi Ou 3,  Min Xu 3,  Lei Ba 3,  Steven S Carroll 3,  Abdellatif El Marrouni 4,  John F Fay 3,  Ashley Forster 4,  Shih Lin Goh 3,  Meigang Gu 5,  Daniel Krosky 3,  Daniel I S Rosenbloom 6,  Payal Sheth 3,  Deping Wang 2,  Guoxin Wu 1,  Matthias Zebisch 5,  Tian Zhao 7,  Paul Zuck 1,  Jay Grobler 1,  Daria J Hazuda 1,  Bonnie J Howell 1,  Antonella Converso 4
Affiliations

Affiliations

  • 1 Infectious Disease and Vaccines, Merck & Co. Inc., Rahway, NJ 07065, USA.
  • 2 Computational and Structural Chemistry, Merck & Co. Inc., Rahway, NJ, 07065, USA.
  • 3 Quantitative Biosciences, Merck & Co. Inc., Rahway, NJ 07065, USA.
  • 4 Discovery Chemistry, Merck & Co. Inc., Rahway, NJ 07065, USA.
  • 5 Evotec Ltd., Abingdon, Oxfordshire OX14 4RZ, UK.
  • 6 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co. Inc., Rahway, NJ 07065, USA.
  • 7 Biostatistics and Research Decision Sciences, Merck & Co. Inc., Rahway, NJ 07065, USA.
PMID: 36812345 DOI: 10.1126/scitranslmed.abn2038
Abstract

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside Reverse Transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+ cell death through premature intracellular viral protease activation. TACK molecules retain potent Antiviral activity and selectively eliminate infected CD4+ T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153225
    98.95%, HIV-1 Inhibitor
    HIV