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Project

Structure-based design of HBV polymerase inhibitors

Cidofovir ((S)-HPMPC), a compound discovered by Antonin Holy, was developed in 1986 for treatment of cytomegalovirus (CMV) retinitis. This compound has a hydroxymethyl substituent engrafted on a phosphonomethoxyethyl (PME) backbone structure. Previously, analogues with a PME backbone as well as phosphonomethoxypropyl nucleoside (PMPA) series were described as active compounds against HIV and Hepatitis B (HBV). The drug activity could arise from the similarities in the active site of their respective polymerases which is targeted by these compounds. The structure-activity relationship of this type of compounds was investigated in order to find compounds with greater specificity. With this in mind, a series of HPMP compounds with a substituent at the tertiary carbon atom was synthesized. One of these compounds, containing a cyano group and a thymine base, was determined as a potent anti-HBV compound, without anti-HIV activity. A second synthesized compound with an ethynyl group and a guanine base, likewise, showed activity against HBV only. These observations indicate potential differences in the active site of HBV polymerase and HIV-RT that can be explored further to discover viral-selective compounds. This points to the fact that a specific base (T or G) is needed in combination with a specific substituent. In this project an experimental 3D structure-based approach will be applied to understand the molecular mechanism of HBV polymerase inhibition by the above nucleosides in order to design more specific inhibitors. Based on high structural and functional similarities between HBV Polymerase (pol) and HIV-RT, HBV pol active region in HIV-RT will be engineered. A recently developed experimental platform for determining structures of HIV-RT by single-particle cryogenic electron microscopy (cryo-EM) will be used. Furthermore, structure solution will be carried out in-house utilizing our recently established state-of-art cryo-EM facility. The obtained structures will guide the synthesis of HBV specific nucleoside analogs and help understand the mechanisms of inhibition and drug resistance.

Date:13 Sep 2021 →  Today
Keywords:synthesis, Structural-based design, nucleosides, HBV, reverse-transcriptase
Disciplines:(Bio)molecular modelling and design
Project type:PhD project