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dc.contributor.advisorCelia A. Schiffer, Ph.D.
dc.contributor.authorRomano, Keith P.
dc.date2022-08-11T08:08:43.000
dc.date.accessioned2022-08-23T16:05:34Z
dc.date.available2022-08-23T16:05:34Z
dc.date.issued2011-05-31
dc.date.submitted2011-10-22
dc.identifier.doi10.13028/2bmp-kp97
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31895
dc.description.abstractHCV 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.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectDrug Resistance
dc.subjectViral
dc.subjectHepacivirus
dc.subjectViral Nonstructural Proteins
dc.subjectProtease Inhibitors
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectChemical Actions and Uses
dc.subjectDigestive System Diseases
dc.subjectPharmaceutical Preparations
dc.subjectTherapeutics
dc.subjectVirology
dc.subjectVirus Diseases
dc.subjectViruses
dc.titleMechanisms of Substrate Recognition by HCV NS3/4A Protease Provide Insights Into Drug Resistance: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1560&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/554
dc.legacy.embargo2012-08-29T00:00:00-07:00
dc.identifier.contextkey2308678
refterms.dateFOA2022-08-30T03:31:24Z
html.description.abstract<p>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.</p> <p>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.</p>
dc.identifier.submissionpathgsbs_diss/554
dc.contributor.departmentBiochemistry and Molecular Pharmacology Program
dc.description.thesisprogramBiochemistry and Molecular Pharmacology


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