Design, synthesis and evaluation of peptidomimetic inhibitors of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) and Middle East respiratory syndrome coronavirus (mers-cov) proteases
type: CreativeWork
description: SARS-CoV-2 and MERS-CoV president the human coronaviruses and zoonotic coronaviruses due to tremendous repercussions to wellbeing of the world population. Investigational efforts focusing on the disease pathology and viral lifecycle have led to identifying multiple druggable targets of both viruses including 3CL protease, PL protease and RNA dependent RNA polymerase. This dissertation summarizes the research findings related to 3CL protease inhibitors of SARS-CoV-2 and MERS-CoV. A structure-guided design approach was used with the aid of X-ray crystallography of inhibitor-3CL protease complexes. The iterative optimization of potency in enzyme assays and cell-based assays yielded inhibitors with nanomolar potency. Multiple inhibitors were found to be highly potent (IC50 < 100 nM) against 3CL proteases of SARS-CoV-2 and MERS-CoV. Inhibitors with dramatically improved antiviral activity in cell-based assays (EC50 = 11-13 nM) against SARS-CoV-2 (chapter 5, compounds 5c/d and 11c/d) were developed. Importantly, these inhibitors specifically target viral lifecycle without causing harmful effects on healthy cells as evidenced by having high safety indices (CC50/EC50 > 1000). Bioisosteric replacement of metabolically vulnerable protons of GC376 with deuterium has led to identification of compound 2 (chapter 1) which showed significantly enhanced survival of SARS-CoV-2 infected K18-hACE2 mice 83 – 100 % compared to 0 % when untreated. Several other drug candidates suitable for conducting further preclinical studies have been identified.
abstract: SARS-CoV-2 and MERS-CoV president the human coronaviruses and zoonotic coronaviruses due to tremendous repercussions to wellbeing of the world population. Investigational efforts focusing on the disease pathology and viral lifecycle have led to identifying multiple druggable targets of both viruses including 3CL protease, PL protease and RNA dependent RNA polymerase. This dissertation summarizes the research findings related to 3CL protease inhibitors of SARS-CoV-2 and MERS-CoV. A structure-guided design approach was used with the aid of X-ray crystallography of inhibitor-3CL protease complexes. The iterative optimization of potency in enzyme assays and cell-based assays yielded inhibitors with nanomolar potency. Multiple inhibitors were found to be highly potent (IC50 < 100 nM) against 3CL proteases of SARS-CoV-2 and MERS-CoV. Inhibitors with dramatically improved antiviral activity in cell-based assays (EC50 = 11-13 nM) against SARS-CoV-2 (chapter 5, compounds 5c/d and 11c/d) were developed. Importantly, these inhibitors specifically target viral lifecycle without causing harmful effects on healthy cells as evidenced by having high safety indices (CC50/EC50 > 1000). Bioisosteric replacement of metabolically vulnerable protons of GC376 with deuterium has led to identification of compound 2 (chapter 1) which showed significantly enhanced survival of SARS-CoV-2 infected K18-hACE2 mice 83 – 100 % compared to 0 % when untreated. Several other drug candidates suitable for conducting further preclinical studies have been identified.
author: Gamachchige, Chamandi S. Dampalla
date published: 2023-05
date modified: 2026-07-24T06:05:48Z
provider: Wichita State University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Wichita State University