SLiM-binding pockets: an attractive target for broad-spectrum antivirals

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2023-05, Vol.48 (5), p.420-427
• Main Authors: Simonetti, Leandro, Nilsson, Jakob, McInerney, Gerald, Ivarsson, Ylva, Davey, Norman E.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Antiviral Agents - pharmacology; inhibitors; Medicin och hälsovetenskap; protein–protein interactions; short linear motifs; viral outbreak preparedness; viruses
• ISSN: 0968-0004; 1362-4326; 1362-4326
• DOI: 10.1016/j.tibs.2022.12.004

Short linear motifs (SLiMs) are compact interaction interfaces indispensable for a variety of cellular processes.Accumulated evidence points at SLiM-binding pockets as a common target for viral hijacking via viral mimicry of host motifs.Recent studies have revealed that blocking SLiM-binding pockets can significantly disrupt the viral life cycle.Targeting human SLiM-binding pockets hijacked by multiple viruses spanning many viral families could allow the development of broad-spectrum antiviral drugs. Short linear motif (SLiM)-mediated interactions offer a unique strategy for viral intervention due to their compact interfaces, ease of convergent evolution, and key functional roles. Consequently, many viruses extensively mimic host SLiMs to hijack or deregulate cellular pathways and the same motif-binding pocket is often targeted by numerous unrelated viruses. A toolkit of therapeutics targeting commonly mimicked SLiMs could provide prophylactic and therapeutic broad-spectrum antivirals and vastly improve our ability to treat ongoing and future viral outbreaks. In this opinion article, we discuss the therapeutic relevance of SLiMs, advocating their suitability as targets for broad-spectrum antiviral inhibitors.