Discovery of Potent DAG-Lactone Derivatives as HIV Latency Reversing Agents
May 22, 2024
Abstract
Toward human immunodeficiency virus type-1 (HIV-1) cure, cells latently infected with HIV-1 must be eliminated from people living with HIV-1. We previously developed a protein kinase C (PKC) activator, diacylglycerol (DAG)-lactone derivative 3, with high HIV-1 latency-reversing activity, based on YSE028 (2) as a lead compound and found that the activity was correlated with binding affinity for PKC and stability against esterase-mediated hydrolysis. Here, we synthesized new DAG-lactone derivatives not only containing a tertiary ester group or an isoxazole surrogate but also several symmetric alkylidene moieties to improve HIV-1 latency reversing activity. Compound 9a, with a dimethyl group at the α-position of the ester group, exerted twice higher HIV-1 latency reversing activity than compound 3, and compound 26, with the isoxazole moiety, was significantly active. In addition, DAG-lactone derivatives with moderate hydrophobicity and potent biostability showed high biological activity.
Journal Article
JOURNAL： ACS Infectious Diseases
TITLE： Discovery of Potent DAG-Lactone Derivatives as HIV Latency Reversing Agents
DOI： https://doi.org/10.1021/acsinfecdis.4c00194
TITLE： Discovery of Potent DAG-Lactone Derivatives as HIV Latency Reversing Agents
DOI： https://doi.org/10.1021/acsinfecdis.4c00194
Correspondence to
Hirokazu Tamamura, Professor
Department of Medicinal Chemistry,
Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University(TMDU)
E-mail:tamamura.mr（at）tmd.ac.jp
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