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Jalily Hasani, Pouria

University of British Columbia

Seasonal and pandemic viral infections continue to pose severe challenges to human health. Antivirals that can effectually complement current vaccination strategies are vital in the battle against drug-resistant pandemic viral strains. Many viruses express small, predominantly hydrophobic and multi-functional proteins that can assemble into oligomeric ion channels capable of passing ions, called viroporins. These small proteins have historically been effective antiviral targets for drugs like amantadine that effectively inhibit the wild-type M2 ion channel of Influenza A. However, drug resistance has rendered adamantane-based antivirals ineffective against circulating strains of influenza A. Similarly, various studies have reported that hexamethylene amiloride (HMA), a previously used diuretic, is also capable of inhibiting the ion channel activity of influenza A M2 and SARS-CoV-1 and 2 Envelope (E) proteins. This dissertation elaborates on the functional properties of a panel of in-house designed and synthesized HMA derivatives and evaluates the activity of these amiloride-derived compounds against known viroporins of influenza A and SARS-CoV-2 through an iterative approach, employing synthetic organic chemistry, electrophysiological measurements and computational techniques and quantification of anti-viral activity through in vitro viral assays. Through studying the structure activity relationship of this chemical class, we report compounds that effectively inhibit the wild-type and adamantane-resistant forms of influenza A M2 ion channel. We found that tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate exhibits dual inhibitory effect against both adamantane-sensitive as well as S31N mutant influenza A M2. This compound has an inhibitory effect against the replication of influenza viruses encoding wild-type M2 and M2(S31N) in vitro. Furthermore, by utilizing in silico techniques such as molecular modelling, docking simulations, molecular dynamics, and steered molecular dynamic, we report that these HMA derivatives are able to bind and effectively block the lumen of SARS-CoV-2 E protein with higher affinity as compared to HMA. Whilst, more work is still needed to utilize these HMA derivatives as therapeutic options, the findings presented in this thesis highlight the potential of amiloride-derived compounds as antivirals against drug-resistant strains of influenza A and important drug leads for the design and further development of inhibitors of SARS-CoV-2 E protein.

Text

2023-02-24

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83857

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/