No Cover Image

Journal article 48 views 9 downloads

Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication

Samantha Rae Wasson, Ben Flude Orcid Logo, Martina Salerno Salerno, Kie Hoon Jung, Gilda Padalino Orcid Logo, Salvatore Ferla Orcid Logo, Dylan Roche-Dugmore, Connor W Bott, Andrea Brancale Orcid Logo, Brian B. Gowen, Marcella Bassetto

ACS Infectious Diseases

Swansea University Authors: Ben Flude Orcid Logo, Martina Salerno Salerno, Gilda Padalino Orcid Logo, Salvatore Ferla Orcid Logo, Dylan Roche-Dugmore

  • 71938.VoR.pdf

    PDF | Version of Record

    © 2026 The Authors. This publication is licensed under CC-BY 4.0 .

    Download (14.06MB)

Check full text

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...

Full description

Published in: ACS Infectious Diseases
ISSN: 2373-8227 2373-8227
Published: American Chemical Society (ACS) 2026
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa71938
first_indexed 2026-05-18T14:56:17Z
last_indexed 2026-05-19T11:19:14Z
id cronfa71938
recordtype SURis
fullrecord <?xml version="1.0"?><rfc1807><datestamp>2026-05-18T16:00:32.1131950</datestamp><bib-version>v2</bib-version><id>71938</id><entry>2026-05-18</entry><title>Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication</title><swanseaauthors><author><sid>436efd85ed59ff6f05f1f1218cbab308</sid><ORCID>0000-0003-2283-3014</ORCID><firstname>Ben</firstname><surname>Flude</surname><name>Ben Flude</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>0ecd6f5c438caf31402b33306fd043ec</sid><firstname>Martina Salerno</firstname><surname>Salerno</surname><name>Martina Salerno Salerno</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>7e5526209f02734f57ba19b0d17604ec</sid><ORCID>0000-0001-8580-1293</ORCID><firstname>Gilda</firstname><surname>Padalino</surname><name>Gilda Padalino</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>d4c62248f510e3b221916989a7bbe6a6</sid><ORCID>0000-0002-5918-9237</ORCID><firstname>Salvatore</firstname><surname>Ferla</surname><name>Salvatore Ferla</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>c66e241df7d061d89c404f989768bad5</sid><firstname>Dylan</firstname><surname>Roche-Dugmore</surname><name>Dylan Roche-Dugmore</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2026-05-18</date><deptcode>EAAS</deptcode><abstract>Pathogenic New World arenaviruses (NWAs), including Jun&#xED;n (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.</abstract><type>Journal Article</type><journal>ACS Infectious Diseases</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>American Chemical Society (ACS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2373-8227</issnPrint><issnElectronic>2373-8227</issnElectronic><keywords>small-molecule antivirals, New World arenaviruses, transferrin receptor 1(TfR1), computer-aideddrug design (CADD), medicinal chemistry</keywords><publishedDay>4</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2026</publishedYear><publishedDate>2026-05-04</publishedDate><doi>10.1021/acsinfecdis.6c00138</doi><url/><notes/><college>COLLEGE NANME</college><department>Engineering and Applied Sciences School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>EAAS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This research was funded by the National Institutes of Health grant R21AI159187 to B.B.G.</funders><projectreference/><lastEdited>2026-05-18T16:00:32.1131950</lastEdited><Created>2026-05-18T15:18:57.5279894</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Pharmacy</level></path><authors><author><firstname>Samantha Rae</firstname><surname>Wasson</surname><order>1</order></author><author><firstname>Ben</firstname><surname>Flude</surname><orcid>0000-0003-2283-3014</orcid><order>2</order></author><author><firstname>Martina Salerno</firstname><surname>Salerno</surname><order>3</order></author><author><firstname>Kie Hoon</firstname><surname>Jung</surname><order>4</order></author><author><firstname>Gilda</firstname><surname>Padalino</surname><orcid>0000-0001-8580-1293</orcid><order>5</order></author><author><firstname>Salvatore</firstname><surname>Ferla</surname><orcid>0000-0002-5918-9237</orcid><order>6</order></author><author><firstname>Dylan</firstname><surname>Roche-Dugmore</surname><order>7</order></author><author><firstname>Connor W</firstname><surname>Bott</surname><order>8</order></author><author><firstname>Andrea</firstname><surname>Brancale</surname><orcid>0000-0002-9728-3419</orcid><order>9</order></author><author><firstname>Brian B.</firstname><surname>Gowen</surname><order>10</order></author><author><firstname>Marcella</firstname><surname>Bassetto</surname><order>11</order></author></authors><documents><document><filename>71938__36784__6e5468dfceaa45d186478d53346a86bd.pdf</filename><originalFilename>71938.VoR.pdf</originalFilename><uploaded>2026-05-18T15:57:20.1089776</uploaded><type>Output</type><contentLength>14740178</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>&#xA9; 2026 The Authors. This publication is licensed under CC-BY 4.0 .</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 2026-05-18T16:00:32.1131950 v2 71938 2026-05-18 Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication 436efd85ed59ff6f05f1f1218cbab308 0000-0003-2283-3014 Ben Flude Ben Flude true false 0ecd6f5c438caf31402b33306fd043ec Martina Salerno Salerno Martina Salerno Salerno true false 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false c66e241df7d061d89c404f989768bad5 Dylan Roche-Dugmore Dylan Roche-Dugmore true false 2026-05-18 EAAS 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. Journal Article ACS Infectious Diseases 0 American Chemical Society (ACS) 2373-8227 2373-8227 small-molecule antivirals, New World arenaviruses, transferrin receptor 1(TfR1), computer-aideddrug design (CADD), medicinal chemistry 4 5 2026 2026-05-04 10.1021/acsinfecdis.6c00138 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University Another institution paid the OA fee This research was funded by the National Institutes of Health grant R21AI159187 to B.B.G. 2026-05-18T16:00:32.1131950 2026-05-18T15:18:57.5279894 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Samantha Rae Wasson 1 Ben Flude 0000-0003-2283-3014 2 Martina Salerno Salerno 3 Kie Hoon Jung 4 Gilda Padalino 0000-0001-8580-1293 5 Salvatore Ferla 0000-0002-5918-9237 6 Dylan Roche-Dugmore 7 Connor W Bott 8 Andrea Brancale 0000-0002-9728-3419 9 Brian B. Gowen 10 Marcella Bassetto 11 71938__36784__6e5468dfceaa45d186478d53346a86bd.pdf 71938.VoR.pdf 2026-05-18T15:57:20.1089776 Output 14740178 application/pdf Version of Record true © 2026 The Authors. This publication is licensed under CC-BY 4.0 . true eng https://creativecommons.org/licenses/by/4.0/
title Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
spellingShingle Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
Ben Flude
Martina Salerno Salerno
Gilda Padalino
Salvatore Ferla
Dylan Roche-Dugmore
title_short Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
title_full Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
title_fullStr Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
title_full_unstemmed Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
title_sort Computer-Aided Discovery of Small-Molecule Inhibitors of Pathogenic New World Arenavirus Entry and Replication
author_id_str_mv 436efd85ed59ff6f05f1f1218cbab308
0ecd6f5c438caf31402b33306fd043ec
7e5526209f02734f57ba19b0d17604ec
d4c62248f510e3b221916989a7bbe6a6
c66e241df7d061d89c404f989768bad5
author_id_fullname_str_mv 436efd85ed59ff6f05f1f1218cbab308_***_Ben Flude
0ecd6f5c438caf31402b33306fd043ec_***_Martina Salerno Salerno
7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
c66e241df7d061d89c404f989768bad5_***_Dylan Roche-Dugmore
author Ben Flude
Martina Salerno Salerno
Gilda Padalino
Salvatore Ferla
Dylan Roche-Dugmore
author2 Samantha Rae Wasson
Ben Flude
Martina Salerno Salerno
Kie Hoon Jung
Gilda Padalino
Salvatore Ferla
Dylan Roche-Dugmore
Connor W Bott
Andrea Brancale
Brian B. Gowen
Marcella Bassetto
format Journal article
container_title ACS Infectious Diseases
container_volume 0
publishDate 2026
institution Swansea University
issn 2373-8227
2373-8227
doi_str_mv 10.1021/acsinfecdis.6c00138
publisher American Chemical Society (ACS)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
document_store_str 1
active_str 0
description 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.
published_date 2026-05-04T17:20:49Z
_version_ 1866631007124324352
score 11.106612

Similar Items