Discovery and mechanism of action of a novel HIV-1 capsid inhibitor, CX06

Peining J. Xu

doi:10.17918/etd-7530

Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic worldwide. Current therapies for HIV-1 are strongly limited not only by the development of multidrug-resistant virus, but also by significant cumulative drug toxicities. Therefore, the development of new classes of antiretroviral drugs with novel targets is highly desirable. In recent years, HIV-1 capsid protein has emerged as a new attractive therapeutic target for the development of novel antivirals due to its structural and regulatory roles. The interaction of the capsid protein both with its self and with host cellular factors is critical to viral replication and infectivity. Structural studies have demonstrated that capsid assembles to form hexamers or pentamers. Both stabilization and destabilization of HIV-1 capsid alter the ability of the virus to complete reverse transcription of its genome in the early stages. Moreover, such stabilization/destabilization also has detrimental effects on the assembly of the virus. Several groups, including our own, are developing inhibitors against this key viral protein. The most widely studied capsid inhibitor, PF-74, has been found to interact with a distinct pocket on the capsid hexamers. This pocket also serves as an interaction site for several host cell factors, making it an attractive site on capsid for small molecule targeting. However, we found that PF-74 is very peptidic and suffers from extremely poor metabolic properties, limiting its use as a drug lead. Therefore, using a combination of high-content pharmacophore based bioisosteric replacement, in silico prediction of drug-like properties, chemical syntheses, and antiviral testing, we have discovered a group of novel HIV-1 inhibitors. Based on the chemical novelty, drug-like properties and antiviral activity, we chose one representative compound, designated CX06, for detailed mechanism of action studies. CX06 can bind capsid directly and inhibit viral replication both at the early and the late stages. As revealed by a competitive binding ELISA, CX06 competes with host factor CPSF6 for binding on capsid hexamer. Through studying viral mutants resistant to CX06, one of the capsid amino acids, Q63, was found to be important for the inhibitory effect of CX06. Mechanistically, CX06 inhibits the capsid assembly and destabilizes the assembled capsid core in vitro. Furthermore, CX06's effect on capsid core stability was demonstrated by inhibiting the products of viral reverse transcription as detected by real-time PCR. We conclude that CX06 is a novel potent HIV-1 capsid inhibitor and is a step towards the clinical realization of capsid inhibitors for HIV-1 treatment, as well as a novel reagent for the study of viral uncoating.

Discovery and mechanism of action of a novel HIV-1 capsid inhibitor, CX06

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Discovery and mechanism of action of a novel HIV-1 capsid inhibitor, CX06

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