Inhibition of Influenza Entry by Organosilicon Compounds

Aleksandar Antanasijevic; Nicholas J Haferman; Amir Shimon; Smanla Tundup; Varada Anirudhan; Lijun Rong; Balaji Manicassamy; Duncan Wardrop; Michael Caffrey

doi:10.1002/jmv.70436

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Inhibition of Influenza Entry by Organosilicon Compounds

Journal article

Open access

Peer reviewed

Inhibition of Influenza Entry by Organosilicon Compounds

Aleksandar Antanasijevic, Nicholas J Haferman, Amir Shimon, Smanla Tundup, Varada Anirudhan, Lijun Rong, Balaji Manicassamy, Duncan Wardrop and Michael Caffrey

Journal of medical virology, Vol.97(6), e70436

06/2025

DOI: 10.1002/jmv.70436

PMCID: PMC12150666

PMID: 40492611

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Abstract

Hemagglutinin (HA) plays a critical role in the entry of influenza and thus HA is a target for the development of entry inhibitors as antivirals. One of the first small molecule inhibitors of influenza entry to be described was tert-butylhydroquinone (TBHQ), a commonly used antioxidant. This compound was shown to inhibit influenza containing Group 2 HA, such as H3 and H7 HA circulating in humans and avians. One limitation of TBHQ is the propensity to oxidize in solution, resulting in a less active form of the compound. Recently, our group has shown that the reactivity of TBHQ may be significantly reduced through substitution of one hydroxyl group with a methoxy, resulting in a concurrent increase in potency and a decrease in cytotoxicity. In this study, we demonstrate that the inhibitory capacity can be further improved by introducing tri-methyl silane (TMS) in place of the tert-butyl (TB) group. Silicon-based derivatives of TBHQ exhibited increased stability in solution compared to the parent TBHQ compound. Analysis using NMR spectroscopy revealed similar interaction patterns for the original and engineered compounds, although the TMS group was creating stronger hydrophobic contacts within the binding pocket on HA. Strikingly, TMS-containing compounds exhibited increased in vitro activity against pseudotyped and live influenza viruses carrying Group 2 HAs. In summary, we applied a novel strategy for chemical optimization of antiviral compounds and demonstrated that this approach can improve their stability and their potency for the target protein.

Animals

Antiviral Agents - chemistry

Antiviral Agents - pharmacology

Dogs

Hemagglutinin Glycoproteins, Influenza Virus - chemistry

Hemagglutinin Glycoproteins, Influenza Virus - metabolism

Humans

Hydroquinones - chemistry

Hydroquinones - pharmacology

Influenza A virus - drug effects

Influenza A virus - physiology

Influenza, Human - virology

Organosilicon Compounds - chemistry

Organosilicon Compounds - pharmacology

Virus Internalization - drug effects

Details

Title: Subtitle: Inhibition of Influenza Entry by Organosilicon Compounds
Creators: Aleksandar Antanasijevic - École Polytechnique Fédérale de Lausanne
Nicholas J Haferman - University of Illinois Chicago
Amir Shimon - University of Illinois Chicago
Smanla Tundup - University of Iowa
Varada Anirudhan - University of Illinois Chicago
Lijun Rong - University of Illinois Chicago
Balaji Manicassamy - University of Iowa
Duncan Wardrop - University of Illinois Chicago
Michael Caffrey - University of Illinois Chicago
Resource Type: Journal article
Publication Details: Journal of medical virology, Vol.97(6), e70436
DOI: 10.1002/jmv.70436
PMID: 40492611
PMCID: PMC12150666
NLM abbreviation: J Med Virol
ISSN: 1096-9071
eISSN: 1096-9071
Publisher: Wiley
Grant note: This study was partially supported by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust to M.C. and B.M. and R01AI127775 to B.M.
Language: English
Date published: 06/2025
Academic Unit: Microbiology and Immunology
Record Identifier: 9984829884202771

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