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

Takahiro Ishii; Takuya Kobayakawa; Kouki Matsuda; Kohei Tsuji; Nami Ohashi; Shingo Nakahata; Airi Noborio; Kazuhisa Yoshimura; Hiroaki Mitsuya; Kenji Maeda; Hirokazu Tamamura

doi:10.1016/j.ejmech.2023.115449

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. Epub 2023 May 3.

Authors

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: tamamura.mr@tmd.ac.jp.

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.

MeSH terms

CD4-Positive T-Lymphocytes / metabolism
Diglycerides
HIV Infections*
HIV-1* / metabolism
Histone Deacetylase Inhibitors / pharmacology
Humans
Protein Kinase C
Virus Activation
Virus Latency

Substances

(1-(hydroxymethyl)-4-(4-methyl-3-(methylethyl)pentylidene)-3-oxo-2-oxolanyl)methyl 4-methyl-3-(methylethyl)pentanoate
Diglycerides
Histone Deacetylase Inhibitors
Protein Kinase C
YSE028

Grants and funding

ZIA SC006738/ImNIH/Intramural NIH HHS/United States