{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:14:00Z","timestamp":1792811640529,"version":"4.5.0"},"reference-count":66,"publisher":"American Chemical Society (ACS)","issue":"52","license":[{"start":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T00:00:00Z","timestamp":1449100800000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM56423"],"award-info":[{"award-number":["GM56423"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI-20201"],"award-info":[{"award-number":["AI-20201"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI74571"],"award-info":[{"award-number":["AI74571"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Influenza virus infections lead to numerous deaths and millions of hospitalizations each year. One challenge facing anti-influenza drug development is the heterogeneity of the circulating influenza viruses, which comprise several strains with variable susceptibility to antiviral drugs. For example, the wild-type (WT) influenza A viruses, such as the seasonal H1N1, tend to be sensitive to antiviral drugs, amantadine and rimantadine, while the S31N mutant viruses, such as the pandemic 2009 H1N1 (H1N1pdm09) and seasonal H3N2, are resistant to this class of drugs. Thus, drugs targeting both WT and the S31N mutant are highly desired. We report our design of a novel class of dual inhibitors along with their ion channel blockage and antiviral activities. The potency of the most active compound 11 in inhibiting WT and the S31N mutant influenza viruses is comparable with that of amantadine in inhibiting WT influenza virus. Solution NMR studies and molecular dynamics (MD) simulations of drug-M2 interactions supported our design hypothesis: namely, the dual inhibitor binds in the WT M2 channel with an aromatic group facing down toward the C-terminus, while the same drug binds in the S31N M2 channel with its aromatic group facing up toward the N-terminus. The flip-flop mode of drug binding correlates with the structure\u2013activity relationship (SAR) and has paved the way for the next round of rational design of broad-spectrum antiviral drugs.<\/jats:p>","DOI":"10.1021\/ja508461m","type":"journal-article","created":{"date-parts":[[2014,12,3]],"date-time":"2014-12-03T15:07:38Z","timestamp":1417619258000},"page":"17987-17995","source":"Crossref","is-referenced-by-count":87,"title":["Flipping\nin the Pore: Discovery of Dual Inhibitors\nThat Bind in Different Orientations to the Wild-Type versus the Amantadine-Resistant\nS31N Mutant of the Influenza A Virus M2 Proton Channel"],"prefix":"10.1021","volume":"136","author":[{"given":"Yibing","family":"Wu","sequence":"first","affiliation":[{"name":"University of California , , Mission Bay Box 3122, , ,","place":["San Francisco, California, United States, 94158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belgin","family":"Canturk","sequence":"additional","affiliation":[{"name":"University of Pennsylvania , , 231 South 34th Street , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunil","family":"Jo","sequence":"additional","affiliation":[{"name":"University of California , , Mission Bay Box 3122, , ,","place":["San Francisco, California, United States, 94158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlong","family":"Ma","sequence":"additional","affiliation":[{"name":"The University of Arizona , , 1501 N. Campbell Avenue , , ,","place":["Tucson, Arizona, United States, 85721"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Gianti","sequence":"additional","affiliation":[{"name":"Temple University , , 1925 North 12th Street , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael L.","family":"Klein","sequence":"additional","affiliation":[{"name":"Temple University , , 1925 North 12th Street , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence H.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Northwestern University , , 2205 Tech Drive , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Lamb","sequence":"additional","affiliation":[{"name":"Northwestern University , , 2205 Tech Drive , , ,","place":["Evanston, Illinois, United States, 60208"]},{"name":"Northwestern University , , , ,","place":["Evanston, Illinois, United States, 60208"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Fiorin","sequence":"additional","affiliation":[{"name":"Temple University , , 1925 North 12th Street , , ,","place":["Philadelphia, Pennsylvania, United States, 19122"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"The University of Arizona , , 1501 N. Campbell Avenue , , ,","place":["Tucson, Arizona, United States, 85721"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[{"name":"University of California , , Mission Bay Box 3122, , ,","place":["San Francisco, California, United States, 94158"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,12,3]]},"reference":[{"key":"2026090217152971400_cit1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.med.51.1.407","volume":"51","author":"Cox","year":"2000","journal-title":"Annu. Rev. Med."},{"key":"2026090217152971400_cit2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1001\/jama.289.2.179","volume":"289","author":"Thompson","year":"2003","journal-title":"JAMA, J. Am. Med.\nAssoc."},{"key":"2026090217152971400_cit3","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1001\/jama.292.11.1333","volume":"292","author":"Thompson","year":"2004","journal-title":"JAMA, J. Am. Med.\nAssoc."},{"key":"2026090217152971400_cit4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1056\/NEJMra0707279","volume":"358","author":"Abdel-Ghafar","year":"2008","journal-title":"N. Engl.\nJ. Med."},{"key":"2026090217152971400_cit5","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/S0140-6736(13)61207-6","volume":"382","author":"Yu","year":"2013","journal-title":"Lancet"},{"key":"2026090217152971400_cit6","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1128\/JVI.06322-11","volume":"86","author":"Xu","year":"2012","journal-title":"J. Virol."},{"key":"2026090217152971400_cit7","doi-asserted-by":"crossref","first-page":"6263","DOI":"10.1021\/jm300455c","volume":"55","author":"Das","year":"2012","journal-title":"J. Med. 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