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Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
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Martina Salerno Salerno,
Kie Hoon Jung,
Gilda Padalino ,
Salvatore Ferla ,
Dylan Roche-Dugmore,
Connor W Bott,
Andrea Brancale ,
Brian B. Gowen,
Marcella Bassetto
ACS Infectious Diseases
Swansea University Authors:
Ben Flude , Martina Salerno Salerno, Gilda Padalino , Salvatore Ferla , Dylan Roche-Dugmore
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DOI (Published version): 10.1021/acsinfecdis.6c00138
Abstract
Pathogenic New World arenaviruses (NWAs), including Junín (JUNV) and Machupo (MACV) viruses, rely on host-virus entry processes that represent attractive points for antiviral intervention. Guided by the known use of human transferrin receptor 1 (hTfR1) by several NWAs for cell entry, we conducted a...
| Published in: | ACS Infectious Diseases |
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| ISSN: | 2373-8227 2373-8227 |
| Published: |
American Chemical Society (ACS)
2026
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa71938 |
| Abstract: |
Pathogenic New World arenaviruses (NWAs), including Junín (JUNV) and Machupo (MACV) viruses, rely on host-virus entry processes that represent attractive points for antiviral intervention. Guided by the known use of human transferrin receptor 1 (hTfR1) by several NWAs for cell entry, we conducted a structure-based virtual screening campaign targeting the MACV GP1-hTfR1 interaction interface to identify small molecules capable of inhibiting early infection. From an screen of commercially available drug-like compounds, 25 candidates were selected and tested in cell-based assays, yielding two chemically distinct scaffolds with low-micromolar activity against JUNV. Hit expansion of the primary chemotype produced 107 new analogues, several of which achieved submicromolar inhibition of JUNV replication. Among them, compound demonstrated antiviral activity across multiple arenaviruses, including both hTfR1-tropic NWAs and viruses that use alternative entry pathways, while showing no effect on the unrelated Rift Valley fever virus. In an hTfR1-expressing mouse model of JUNV infection, was well tolerated, but did not confer protection. These results provide the foundation for further development and optimization of potent compounds that broadly inhibit infection by the pathogenic NWAs. |
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| Keywords: |
small-molecule antivirals, New World arenaviruses, transferrin receptor 1(TfR1), computer-aideddrug design (CADD), medicinal chemistry |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was funded by the National Institutes of Health grant R21AI159187 to B.B.G. |