Журнал инфекционных заболеваний и терапии

Абстрактный

Search for Low Molecular Weight Compounds that Inhibit Human Immunodeficiency Virus Type 1 Replication

Chris Verathamjamras, Yu-Shi Tian, Norihito Kawashita, Kousuke Okamoto, Teruo Yasunaga, Kazuyoshi Ikuta, Kazushi Motomura, Naokazu Takeda, Tatsuya Takagi,  Masanori Kameoka

Highly active antiretroviral (ARV) therapy has successfully reduced viral transmission, morbidity, and mortality associated with human immunodeficiency virus type 1 (HIV-1) disease; however, the emergence of drug-resistant viruses is a major obstacle associated with ARV therapy. Therefore, the development of a new class of ARV drugs is urgently required. Cyclophilin A (CypA) is a host factor required for HIV-1 replication, and plays a role in viral replication by interacting with the HIV-1 capsid protein (CA). As such, it represents a potential target for novel ARV drugs. We here searched for low molecular weight compounds that inhibited HIV-1 replication by interfering with binding between CypA and HIV-1 CA. A total of 106 compounds were screened in an in silico docking study as candidates that were predicted to interact with the HIV-1 CA binding pocket of CypA. Biological tests were then conducted to evaluate the anti-HIV-1 activities as well as cytotoxicities of these test compounds, and 4 compounds that efficiently inhibited viral replication without exhibiting strong cytotoxicity were subsequently selected. The molecular mechanisms underlying the inhibition of HIV-1 replication by the 4 selected compounds have not been elucidated in the present study; however, we consider that these compounds will become the lead compounds for developing novel ARV drugs once more detailed studies are performed on the molecular mechanisms responsible for their anti-HIV-1 activities.