Major
Pharm.D. (six years)
Minor(s)
Leadership Studies
Advisor
Cho, Bongsup
Advisor Department
Pharmacy Practice (PHP)
Date
5-2021
Keywords
3D visualization; 3C-like protease, peptidomimetic virus; zoonotic virus
Abstract
Zoonotic viruses, including coronaviruses, Ebola virus, HIV, influenza, and more, are ubiquitous and can emerge as significant human pathogens capable of global epidemics and pandemics. Most often, researchers spend their time and resources targeting only the human pathogens and developing therapeutic compounds to treat the associated diseases. However, a missed opportunity is targeting the zoonotic host instead and aiming to acquire the chemical and structural knowledge to inform us of the evolutionary path of the virus. The bat coronavirus HKU4 belongs to the same lineage as the Middle East Respiratory Syndrome coronavirus (MERS-CoV) and shows high sequence similarity. This is a threat to the human population if there ever is a zoonotic shift event. Before the current Covid-19 pandemic, there were no effective vaccines or antiviral treatments that were capable of limiting the pathogenesis of any human coronaviral infection. However, an attractive target for the development of antibodies is the 3C-like protease (3CLpro), which is essential for the progression of the virus life cycle. A private study was done where 230 peptidomimetic compounds were chosen to inhibit HKU4-CoV 3CLpro, out of which 43 peptidomimetic compounds had good to excellent potency. The favored backbone for inhibition contained 3-thiophene and 1-methylbenzotriazole. For my project, I picked the best, most potent out of those inhibitors (also known as 1A) and designed it on a powerful molecule visualization program, Chimera. Through science visualization and molecular modeling, I 3D printed this molecule and we can watch from a 360 degree angle how the 1A inhibitor is interacting with the 3CL protease, therefore inhibiting further replication of the virus. In the future, the favored backbone can be used to design compounds with the ability to fully exploit the active site, hopefully leading to selective and potent inhibitors against human pathogens like SARS and MERS.