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
  • 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.

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