Date of Completion

2023

Document Type

Thesis

Degree Name

Bachelor of Science in Biochemistry

Keywords

Apratoxin S4, SARS-CoV-2, Sec61, co-translational translocation, in silico methods

Abstract

The virus for COVID-19 enters the cell by attaching to a receptor in the cell membrane called angiotensin-converting enzyme 2 (ACE2). ACE2 is a protein that is transported into the rough ER through the Sec61 translocon for protein folding as it gets translated. Sec61 inhibitors are currently being researched in anti-cancer treatment. As viruses hijack cellular pathways for their own proteins, Sec61 inhibitors like apratoxins is investigated as potential COVID-19 therapeutics that can handle future SARS-CoV-2 variants. Reported herein are the binding of derivatives designed in silico from Apratoxin S4 (Apra S4) as well as signal peptides of selected secretory proteins to Sec61 docked using HADDOCK web software. With it being a broad-spectrum inhibitor blocking many proteins, the derivatives were designed to have a more positive binding energy than Apra S4 (-9.17 kcal/mol) while maintaining a spontaneous binding signified by a negative value. Designed compound GHA8 acquired the most positive binding (-8.01 kcal/mol), but compounds CA10 (-8.49 kcal/mol), ECC9 (-8.24 kcal/mol), and GHA7 (-8.26 kcal/mol) were the most drug-like derivatives among the 10 best binding based on the oral bioavailability and toxicity predictions. Specifically, CA10, ECC9, ECC10, and GHA7 had less violations in the proposed physiochemical guidelines for oral macrocyclic drugs than Apra S4 while all derivatives reported had better synthetic accessibility scores. CA9 and ECC10 were the only derivatives in top 10 that were more toxic (Toxicity Class III) than Apra S4 (Toxicity Class IV). The reduced binding affinity may limit the inhibited proteins and make Sec61 inhibitors more suitable for viral treatment. The results of this study can be used to further investigate derivatives of Sec61 inhibitors for antiviral activity in vitro/vivo. Future researchers may propose mechanisms for the synthesis of designed derivatives or confirm the inhibited proteins in cell lines. The compounds can also be tested against SARS-CoV-2 variants to evaluate their antiviral properties.

First Advisor

Margel C. Bonifacio

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