Drug Resistance in HCV NS3/4A and Beyond - Inhibitor Binding versus Substrate Recognition In the last 3-5 years the treatment of Hepatitis C Virus (HCV) has been revolutionize by direct- acting antivirals (DAAs). NS3/4A protease was the first target for HCV where DAAs were developed. NS3/4A protease inhibitors (PIs) continue to be key components in the development of therapeutic options including combination therapies currently in phase 3 clinical trials. While the current PIs are highly potent against wil-type genotype 1 HCV, the rapid evolution of HCV and genotypic differences around the world allow viable variants with often multiple mutations that are resistant against these PIs, and decrease their effectiveness. Drug resistance is caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the therapeutic target. Disrupting the therapeutic target's activity is necessary but nt sufficient for avoiding resistance. We hypothesize that the impact of multiple mutations selected under the pressure of PI therapy or in different genotypes is not simply additive, but these mutations have interdependent effects causing structural and dynamic changes to confer resistance. We will elucidate the molecular mechanisms by which resistance occurs in HCV NS3/4A, and develop and implement strategies to design new inhibitors less susceptible to resistance. One key strategy is to compare inhibitor binding to substrate recognition and avoid functionally unessential contacts that are vulnerable to resistance mutations. The strategies we develop to design potent inhibitors less susceptible to resistance will also be translated to flaviviral proteases such as dengue, where no current DAA or vaccine exists.

Public Health Relevance

In the last 3-5 years the treatment of Hepatitis C Virus (HCV) has been revolutionize by direct-acting antivirals (DAAs). NS3/4A protease was the first target for HCV where DAAs were developed. NS3/4A protease inhibitors (PIs) continue to be key components in the development of therapeutic options including combination therapies currently in phase 3 clinical trials. While the current PIs are highly effective in most cases, the rapid evolution of HCV and genotypic differences around the world allow viable variants resistant against these PIs. We will reveal the molecular basis of this resistance and develop strategies to design novel more robust HCV PIs. One key strategy is to compare inhibitor binding to substrate recognition and avoid functionally unessential contacts that are vulnerable to resistance mutations. The strategies to design potent inhibitors less susceptible to resistance will also be translated to flaviviral proteases such as dengue, where no current DAA or vaccine exists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085051-08
Application #
9193516
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Koshy, Rajen
Project Start
2010-05-01
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Rusere, Linah N; Matthew, Ashley N; Lockbaum, Gordon J et al. (2018) Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants. ACS Med Chem Lett 9:691-696
Matthew, Ashley N; Kurt Yilmaz, Nese; Schiffer, Celia A (2018) Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C InfectionPublished as part of the Biochemistry series ""Biochemistry to Bedside"". Biochemistry 57:481-482
Matthew, Ashley N; Leidner, Florian; Newton, Alicia et al. (2018) Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease. Structure 26:1360-1372.e5
Matthew, Ashley N; Zephyr, Jacqueto; Hill, Caitlin J et al. (2017) Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants. J Med Chem 60:5699-5716
Lin, Kuan-Hung; Ali, Akbar; Rusere, Linah et al. (2017) Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side. J Virol 91:
Kurt Yilmaz, Nese; Swanstrom, Ronald; Schiffer, Celia A (2016) Improving Viral Protease Inhibitors to Counter Drug Resistance. Trends Microbiol 24:547-557
Soumana, Djadé I; Kurt Yilmaz, Nese; Prachanronarong, Kristina L et al. (2016) Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172. ACS Chem Biol 11:900-9
Lin, Kuan-Hung; Nalivaika, Ellen A; Prachanronarong, Kristina L et al. (2016) Dengue Protease Substrate Recognition: Binding of the Prime Side. ACS Infect Dis 2:734-743
Soumana, Djadé I; Kurt Yilmaz, Nese; Ali, Akbar et al. (2016) Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease. J Am Chem Soc 138:11850-9
Ndjomou, Jean; Corby, M Josie; Sweeney, Noreena L et al. (2015) Simultaneously Targeting the NS3 Protease and Helicase Activities for More Effective Hepatitis C Virus Therapy. ACS Chem Biol 10:1887-96

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