Document Type
Dissertation
Date of Award
5-2022
School/College
College of Pharmacy and Health Sciences (COPHS)
Degree Name
Ph.D. in Pharmaceutical Science
Committee Chairperson
Omonike Olaleye
Committee Member 1
Dong Liang
Committee Member 2
Ya Fatou Njie Mbye
Committee Member 3
Miranda Hector
Keywords
ACE2, COVID-19, Delta Variant, Drug Discovery, SARS-CoV-2, Treatment
Abstract
The current pandemic of coronavirus disease (COVID-19) caused by the highly infectious pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global public health challenge. The emergence of deadly SARS-CoV-2 variants with mutations on the viral genes has made it more imperative to discover therapeutics that target the host receptors for COVID-19 treatment. Therefore, our research has targeted the critical host entry receptors: Angiotensin-converting enzyme-2 (ACE2) for SARS-CoV-2 entry into the human cells. SARS-CoV-2 is an enveloped RNA beta coronavirus that infects human cells via interaction with the ACE2 receptor, followed by viral replication and virus dissemination. Spike protein of SARS-CoV-2 has a receptor-binding domain (RBD), which binds to the host ACE2 receptor. ACE2 is an essential component of the Renin-Angiotensin system that converts Angiotensin II (Ang II) to Angiotensin 1-7, a potent vasopressor. Even though ACE2 facilitates viral entry, it provides defense against acute lung injury, indicating that the ACE2/Ang 1-7 pathway must be carefully manipulated to reduce SARS-CoV-2 induced lung injuries. Herein, we discovered that OJT010 targets the interaction between RBD and rhACE2 without inactivating the exopeptidase activity of rhACE2. Our findings reveal that OJT010 binding to rhACE2 may preserve its physiological function and prevention exacerbation of the disease. Furthermore, it will potentially prevent non-target cardiac toxicities observed in other ACE2 modulating drugs. Moreover, we discover that OJT010 inhibits the cellular entry and further replication of the SARS-CoV-2 and B.1.617.2 Delta Variant in three individual assays; Infection Induced Cytopathic Effect (CPE), Nanoluciferase reporter assay (NLRV), and Pseudotyped Lentiviral assay. In addition, we have also assessed the molecular interactions of the compounds with the host and viral receptor using molecular dynamic simulation of the best-fit docking complex to elucidate the binding sites of OJT010. Next, we have determined the pharmacokinetics (PK) parameters of OJT010 in healthy rats. We have further advanced into a hamster of model SARS-CoV-2 infection to evaluate the efficacy of OJT010 against SARS-COV-2 infection in vivo. Based on our findings, OJT010 represents a promising drug class that could be further evaluated as a lead series in developing chemotherapeutics for COVID-19 treatment.
Copyright
Copyright © for this work is retained by the author. Any documents and information presented are protected by copyright under US Copyright laws and are the property of the author. All Rights Reserved. For permission to use this content please contact the author or the Graduate School at Texas Southern University (graduate.school@tsu.edu).
Recommended Citation
Kaur, Manvir, "Discovery of OJT010 as a Novel Inhibitor of Severe Acute Respiratory Syndrome Coronavirus 2" (2022). Dissertations (2016-Present). 16.
https://digitalscholarship.tsu.edu/dissertations/16