Date of Award
College of Pharmacy and Health Sciences (COPHS)
Ph.D. in Pharmaceutical Science
Omonike A. Olaleye
Committee Member 1
Committee Member 2
Ya Fatou Mbye
Committee Member 3
• ACE 2 • COVID-19 • Drug Discovery • Infectious Diseases • Molecular Biology • SARS-CoV-2
The emergence of deadly SARS-CoV-2 variants with mutations in the viral genes has made it more imperative to discover therapeutics that target the host receptors for coronavirus disease (COVID-19) treatment. SARS-CoV-2 spike protein receptor-binding domain (RBD) binds to host ACE2 receptor, facilitating viral entry (Jackson, 2022). The Interaction between ACE2 and the RBD region of Spike protein is the most crucial step in the viral life cycle. Therefore, the ACE2- RBD interaction has remained a key target for therapeutics in COVID19 treatment. Therefore, our research has targeted this interaction to prevent SARS-CoV-2 entry into the human cells. ACE2, a key component of the Renin-Angiotensin system, normally converts Angiotensin II (Ang II) to Angiotensin 1-7, which has potent vasopressor effects. Despite ACE2's role in facilitating viral entry, it also plays a defensive role against acute lung injury. This highlights the importance of carefully modulating the ACE2/Ang 1-7 pathway to mitigate lung damage caused by SARS-CoV-2 infection. It is crucial to strike a balance between viral entry and preserving the protective functions of the ACE2/Ang 1-7 pathway to minimize SARS-CoV-2-induced lung injuries. we discovered that OJT009 targets the interaction between RBD and rhACE2 by binding to the exopeptidase site of rhACE2 Our findings reveal that the binding of OJT009 to rhACE2 inhibits its exopeptidase activity at high concentrations, but further investigations through western blot analysis and semi quantitative RT-PCR show that it does not affect rhACE2 protein and gene expression and those same concentrations. Additionally, it has the potential to mitigate non-target cardiac toxicities that have been observed with other drugs that modulate ACE2. Furthermore, our findings demonstrate that OJT009 effectively inhibits the cellular entry and subsequent replication of both SARS-CoV-2 and the B.1.617.2 Delta Variant, as evidenced by three distinct assays: the Infection Induced Cytopathic Effect (CPE), Nanoluciferase reporter assay (NLRV), and Pseudotyped Lentiviral assay. Also, through molecular dynamic simulation and the analysis of best-fit docking complexes, we have elucidated the binding sites of OJT009 and examined its molecular interactions with both host and viral receptors. Based on our findings, OJT009 presents a whole new potential pharmacophore for preclinical drug development against SARS-CoV-2 infection.
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Adebusuyi, Tolulope Olayinka, "Discovery of OJT009 as a Novel Inhibitor of Severe Acute Respiratory Syndrome Coronavirus 2 Infection for Potential Treatment Of C0VID-19" (2023). Dissertations (2016-Present). 76.