Identification Of SARS-CoV-2 Main Protease Inhibitors
Utilizing Michael Acceptor Warheads
My Oral Presentation at Northern California and Western Nevada Junior Science and Humanities Symposium.
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Independent Researcher, September 2020 - Present
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Competitions and Awards
1. BioGENEius Challenges, Biotechnology Institute, Washington, DC, 2021
- Qualifier | Participant, U.S. International BioGENEius Challenge
- Finalist, Global Healthcare Challenge Category, the Bay Area BioGENEius Challenge
* Recognition Award: $1,000
2. Junior Science and Humanities Symposium (JSHS), 2020 - 2021
- Semifinalist (Top 12 in region), Northern California & Western Nevada Regional
Junior Science and Humanities Symposium, January 2021
3. Contra Costa County Science and Engineering Fair, CA, 2020 - 2021
- 2nd place in Biology Category
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Advisors
1. Dr. Alden Blair, Ph.D., University of California San Francisco, San Francisco, CA;
Science Teacher, The College Preparatory School, Oakland, CA.
* Supported competitions preparation, manuscript development and data analysis.
2. Dr. Gulam Rather, Ph.D., Mentor, Junior Academy of the Global STEM Alliance;
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
* Provided inputs for study design and methodology.
3. Edward Njoo, Ph.D. Student in Chemistry, Stanford University, Stanford, CA.
* Introduced the fundamental knowledge and methodology of COVID-19 inhibitor
development.
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Submission for Publication in Progress
I was named as "U.S. International BioGENEius Challenge 2021 Finalist" (I was in Video [3:33-3:36, 4:54-5:04, 8:34-8:39, 9:23-9:32, 9:54-9:57, 11:00-11:10, 15:35-16:00, 17:42-17:49, 18:06-18:09]).
I participated "2021 U.S. International BioGENEius Challenge Roundtable" meeting (I was in Video [0:19-0:22, 19:43-20:14]).
ABSTRACT
Since December of 2019, the novel coronavirus (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has manifested into a global health emergency. Salient issues with existing vaccines and drug development include immune response durability, viral mutations, and future strings of coronaviruses. This has intensified the eminent need for novel broad-spectrum antivirals targeting coronaviruses based on shared motifs of their pathogenesis. A common target among coronaviruses is the viral main protease (Mpro) due to its essential role in RNA replication. Antivirals targeting the SARS-CoV-2 Mpro are often α-ketoamide inhibitors, a class of Michael acceptor compounds. However, these existing compounds are insufficiently potent to justify further in vitro and in vivo studies. On the basis of the Michael acceptor, I rationally designed and computationally screened a library of compounds against the Mpro. Compound design strategically selected 7 alternative electron-withdrawing group classes (EWGs) and 8 amino acid pairing modifications based on viral pathogenesis, compound structure-activity relationships, and drug-receptor binding mechanisms to combinatorically create a library of 56 Michael acceptors. Swissdock was utilized to screen the compounds against the SARS-CoV-2 Mpro. ANOVA and Tukey-Kramer multiple comparisons were performed across the 7 EWG classes and 8 amino acid pairings. My results suggested that compounds containing sulfone and amide EWGs and arginine amino acids have significantly higher binding affinity than the α-ketoamide, making them viable antivirals for further in vitro and in vivo investigation. These identified modifications also enhance the reactivity of existing Michael acceptor inhibitors, allowing for the optimization of existing drugs to improve their potency. Furthermore, given high Mpro amino acid sequence similarity across different species of β-coronaviruses, my approach can be applied to other pathogenic β-coronaviruses towards potential broad-spectrum antivirals. [Full Article Link]
