2. Academic Validation
  3. Synthesis and evaluation of DAG-lactone derivatives with HIV-1 latency reversing activity

Synthesis and evaluation of DAG-lactone derivatives with HIV-1 latency reversing activity

  • Eur J Med Chem. 2023 Aug 5;256:115449. doi: 10.1016/j.ejmech.2023.115449.
Takahiro Ishii 1,  Takuya Kobayakawa 1,  Kouki Matsuda 2,  Kohei Tsuji 1,  Nami Ohashi 3,  Shingo Nakahata 4,  Airi Noborio 5,  Kazuhisa Yoshimura 6,  Hiroaki Mitsuya 7,  Kenji Maeda 5,  Hirokazu Tamamura 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo, 101-0062, Japan.
  • 2 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan; AIDS Clinical Center, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo, 162-8655, Japan.
  • 3 Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
  • 4 Division of HTLV-1/ATL Carcinogenesis and Therapeutics, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan.
  • 5 Division of Antiviral Therapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, 890-8544, Japan.
  • 6 Institute of Public Health, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government, Shinjuku-ku, Tokyo, 169-0073, Japan.
  • 7 Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku-ku, Tokyo, 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States; Department of Clinical Sciences, Kumamoto University Hospital, Chuo-ku, Kumamoto, 860-8556, Japan.
  • 8 Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), Chiyoda-ku, Tokyo, 101-0062, Japan. Electronic address: [email protected].
PMID: 37224601 DOI: 10.1016/j.ejmech.2023.115449
Abstract

Cells latently infected with human immunodeficiency virus type 1 (HIV-1) prevent people living with HIV-1 from obtaining a cure to the infectious disease. Latency reversing agents (LRAs) such as protein kinase C (PKC) activators and histone deacetylase (HDAC) inhibitors can reactivate cells latently infected with HIV-1. Several trials based on treatment with HDAC inhibitors alone, however, failed to reduce the number of latent HIV-1 reservoirs. Herein, we have focused on a diacylglycerol (DAG)-lactone derivative, YSE028 (1), which is a PKC Activator with latency reversing activity and no significant cytotoxicity. Caspase-3 activation of YSE028 (1) led to cell Apoptosis, specifically in HIV-1 latently infected cells. Structure-activity relationship studies of YSE028 (1) have produced several useful derivatives. Among these, compound 2 is approximately ten times more potent than YSE028 (1) in reactivation of cells latently infected with HIV-1. The activity of DAG-lactone derivatives was correlated with the binding affinity for PKC and the stability against esterase-mediated hydrolysis.

Keywords

DAG-Lactone; HIV cure; PKC activator; Shock and kill.

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