Objev, návrh a charakterizace nových nepeptidových inhibitorů HIV-1 proteázy

Kožíšek, Milan

Ph.D. thesis abstract Overcoming drug resistance : The discovery, design and characterization of new nonpeptidic inhibitors of HIV-1 protease Milan Kožíšek, M.Sc. Supervisor : Jan Konvalinka, Ph.D. PPrraagguuee 22001100 Department of Biochemistry Faculty of Science Charles University, Prague, Czech Republic Institute of Organic Chemistry and Biochemistry Gilead Sciences & IOCB Research Centre Academy of Sciences of the Czech Republic 3 Abstract HIV-1 protease is an aspartic protease which plays an essential role in the life cycle of HIV virus. It is responsible for the cleavage of the viral polyproteins into the structural and functional proteins during viral maturation. The efficient inhibition of the protease thus leads to the formation of immature and non-infectious viral particles. The introduction of protease inhibitors dramatically changed the treatment of retroviral infection. The viral replication was reduced to undetectable level and the rate of disease progression was significantly lowered. However, resistance to the inhibitors was observed. The first inhibitors had limited bioavailability, caused severe side effects and easily developed resistance. To combat these negative factors, second-generation inhibitors have been developed. Understanding the mechanisms of resistance toward inhibitors is...

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