Chronic liver disease kills an estimated 1000 people in the US every year and is caused in 40 percent of cases, by the hepatitis C virus. This virus has a positive strand RNA as its genome and a highly error prone NS5B RNA-dependent RNA polymerase for genomic replication. As a consequence, HCV has rapidly evolved with six genotypes and more than 14 sub-genotypes. Great efforts have been made to develop effective direct acting antivirals (DAA), however, by focusing on genotype 1a, the most predominant in western countries, we have neglected about 30 percent of people infected with HCV and moreover, victims found in third world countries. The heterogeneity of the virus has clearly set limitations to the discovery of a pan-genotypic DAA. That being said, I propose that by understanding the differences in substrate recognition of the most divergent HCV NS3/4A protease, we can get one step closer to designing an inhibitor that satisfies two major properties: 1) the inhibitor must fit within the overall substrate envelope of all HCV NS3/4A protease;2) the inhibitor must exhibit a very low susceptibility to drug resistance. To that end, crystal structures of the protease domain of HCV NS3/4A from various genotypes will be determined in complex with their natural substrates and inhibitors.
Hepatitis C infects an estimated 170 million people worldwide, new drugs called protease inhibitors are coming on the market but are only effective on patients in the west. I plan to study the molecular interactions of these drugs in forms of the virus that predominantly infect the rest of the world, with the hope of developing more effective drugs.
|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:|
|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|
|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|
|Soumana, Djadé I; Ali, Akbar; Schiffer, Celia A (2014) Structural analysis of asunaprevir resistance in HCV NS3/4A protease. ACS Chem Biol 9:2485-90|
|Ali, Akbar; Aydin, Cihan; Gildemeister, Reinhold et al. (2013) Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol 8:1469-78|
|Romano, Keith P; Ali, Akbar; Aydin, Cihan et al. (2012) The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog 8:e1002832|