Mechanisms of Substrate Recognition by HCV NS3/4A Protease Provide Insights Into Drug Resistance: A Dissertation
Authors
Romano, Keith P.Faculty Advisor
Celia A. Schiffer, Ph.D.Academic Program
Biochemistry and Molecular PharmacologyUMass Chan Affiliations
Biochemistry and Molecular Pharmacology ProgramDocument Type
Doctoral DissertationPublication Date
2011-05-31Keywords
Drug ResistanceViral
Hepacivirus
Viral Nonstructural Proteins
Protease Inhibitors
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Chemical Actions and Uses
Digestive System Diseases
Pharmaceutical Preparations
Therapeutics
Virology
Virus Diseases
Viruses
Metadata
Show full item recordAbstract
HCV afflicts many millions of people globally, and antiviral therapies are often ineffective and intolerable. The Food and Drug Administration approved the HCV protease inhibitors telaprevir and boceprevir in May 2011, marking an important milestone in anti-HCV research over the past two decades. Nevertheless, severe drug side effects of combination therapy – flu-like symptoms, depression and anemia – limit patient adherence to treatment regimens. The acquisition of resistance challenges the long-term efficacy of antiviral therapies, including protease inhibitors, as suboptimal dosing allows for the selection of drug resistant viral variants. A better understanding of the molecular basis of drug resistance is therefore central to developing future generation protease inhibitors that retain potency against a broader spectrum of HCV strains. To this end, my research characterizes the molecular basis of drug resistance against HCV protease inhibitors. Chapter II defines the mode of substrate recognition by the common volume shared by NS3/4A substrate products – the substrate envelope. Chapter III then correlates patterns of drug resistance to regions where drugs protrude from the substrate envelope. Lastly, Chapter IV elucidates the molecular underpinnings of resistance against four leading protease inhibitors – telaprevir, danoprevir, vaniprevir and MK-5172 – and provides practical approaches to designing novel drugs that are less susceptible to resistance. I ultimately hope my work appeals to the broader biomedical community of virologists, medicinal chemists and clinicians, who struggle to understand HCV and other human pathogens in the face of rapid disease evolution.DOI
10.13028/2bmp-kp97Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31895Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/2bmp-kp97