tetano
Editor, Senior Moderator
Sci Adv
. 2026 Nov 6;12(45):eaei8633.
doi: 10.1126/sciadv.aei8633. Epub 2026 Nov 6.
Charley Mackenzie-Kludas 1 , Wen-Yang Wu 2 , Betty Jin 2 , Jennifer L McKimm-Breschkin 1 , Ee Ling Seah 2 , Paul Jones 2 , Emily Fairmaid 1 , Celeste M K Tai 3 , Ding Yuan Oh 3 , Peter J Jenkins 2 , Aeron C Hurt 3 , Lorena E Brown 1 4
Affiliations Expand
While contemporary antiviral development primarily strives to produce "lock and key" inhibitors, we present here a different approach to drug design that uses compounds devised to alter the microenvironment of the virion surface, making it incompatible with virus entry. We illustrate this strategy with inhibitors of influenza virus and show that compounds designed to produce a proton-rich mantle above the virion surface affect the ability of the viral hemagglutinin to interact with cellular receptors and gain entry to the cell. The compounds show exceptional antiviral activity both in vitro and in vivo and protect against influenza illness in ferrets and in mice after a single dose, either therapeutically or prophylactically.
. 2026 Nov 6;12(45):eaei8633.
doi: 10.1126/sciadv.aei8633. Epub 2026 Nov 6.
Dual-acting compounds that deliver an acidifying domain via zanamivir to the virus surface are potent influenza inhibitors
Charley Mackenzie-Kludas 1 , Wen-Yang Wu 2 , Betty Jin 2 , Jennifer L McKimm-Breschkin 1 , Ee Ling Seah 2 , Paul Jones 2 , Emily Fairmaid 1 , Celeste M K Tai 3 , Ding Yuan Oh 3 , Peter J Jenkins 2 , Aeron C Hurt 3 , Lorena E Brown 1 4
Affiliations Expand
- PMID: 42993849
- PMCID: PMC13742177
- DOI: 10.1126/sciadv.aei8633
Abstract
While contemporary antiviral development primarily strives to produce "lock and key" inhibitors, we present here a different approach to drug design that uses compounds devised to alter the microenvironment of the virion surface, making it incompatible with virus entry. We illustrate this strategy with inhibitors of influenza virus and show that compounds designed to produce a proton-rich mantle above the virion surface affect the ability of the viral hemagglutinin to interact with cellular receptors and gain entry to the cell. The compounds show exceptional antiviral activity both in vitro and in vivo and protect against influenza illness in ferrets and in mice after a single dose, either therapeutically or prophylactically.