GSK3739936 is a Potent HIV-1 Allosteric Integrase Inhibitor

HIV-1 integrase (IN) is an enzyme responsible for integrating the viral DNA copy of the viral RNA genome into the host chromatin. Specifically, IN is one of the main anti-virus targets. Besides, HIV-1 IN consists of three different structural and functional domains: N-terminal domain, catalytic core domain (CCD), and C-terminal domain. All clinically available HIV-1 IN inhibitors need catalytic sites of metal ions for the enzymatic reaction of IN. It mainly blocks the chain transfer activity of IN. In the process of viral integration, HIV-1 hijacks a host transcription regulator protein, LEDGF/p75. Moreover, the protein is preferentially integrated into the active transcription unit.

Furthermore, integrating the DNA copy of HIV RNA genome into the host chromatin is a key step in HIV replication. Meanwhile, IN plays a second key role in HIV-1 replication. Specifically, IN directly interacts with the viral RNA genome during the morphogenesis of viral particles. Nonetheless, HIV-1 integrase (IN) is critical to viral replication and is an important multifunctional therapeutic target. Allosteric HIV-1 integrase inhibitors (ALLINI) are a promising new class of antiretroviral drugs. They can destroy the normal maturation of viruses by inducing hyperpolymerization of IN. Chain transfer inhibitor (INSTI) is a component of antiretroviral therapy for HIV-1 infected people. Here, we will introduce a potent HIV-1 allosteric integrase inhibitor, GSK3739936 (BMS-986180).

GSK3739936 is a potent HIV-1 allosteric Integrase inhibitor.

From: Trivedi J, et al. Curr HIV/AIDS Rep. 2020 Feb;17(1):63-75.

At first, GSK3739936 is a potent HIV-1 allosteric integrase inhibitor with an IC50 value of 11.1 nM and an EC50 value of 1.7 nM. Importantly, GSK3739936 is also a weak CYP inhibitor (IC50>24.3 μM). Particularly, GSK3739936 shows favorable pharmacokinetic properties in preclinical species with rapid absorption. It has low to moderate clearance and excellent oral bioavailability.

Secondly, GSK3739936 is not cytotoxic to MT-2 cells, exhibiting CC50 values of >20 μM. GSK3739936 exhibits a low clearance in the mouse, rat, and dog with moderate to long elimination half-lives. Interestingly, GSK3739936 displays moderate clearance and a short elimination half-life in the cynomolgus monkey. The absolute oral bioavailability ranges between 52 and 89%. In particular, the tmax value is 2-5 h, suggesting rapid absorption in all four species.

Finally, GSK3739936 is a potent HIV-1 allosteric integrase inhibitor.


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