{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:29:27Z","timestamp":1790994567865,"version":"4.1.0"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,12,26]],"date-time":"2020-12-26T00:00:00Z","timestamp":1608940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Avisa Pharmaceuticals LLC"},{"name":"Chemical Diversity Research Institute"},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centers of Excellence for Influenza Research and Surveillance","award":["HHSN272201400006C"],"award-info":[{"award-number":["HHSN272201400006C"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The development and clinical implementation of the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil was a breakthrough in influenza therapy, but it was associated with the emergence of drug-resistant variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To design and synthesize structural analogues of CEN inhibitors and evaluate their safety, pharmacokinetics and antiviral potency in vitro and in vivo.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The drug candidate AV5124 and its active metabolite AV5116 were synthesized based on pharmacophore modelling. Stability in plasma and microsomes, plasma protein binding, cytotoxicity and antiviral activities were assessed in vitro. Pharmacokinetics after IV or oral administration were analysed in CD-1 mice. Acute toxicity and protective efficacy against lethal A(H1N1)pdm09 influenza virus challenge were examined in BALB\/c mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Pharmacophore model-assisted, 3D molecular docking predicted key supramolecular interactions of the metal-binding group and bulky hydrophobic group of AV5116 with the CEN binding site (Protein Data Bank code: 6FS6) that are essential for high antiviral activity. AV5116 inhibited influenza virus polymerase complexes in cell-free assays and replication of oseltamivir-susceptible and -resistant influenza A and B viruses at nanomolar concentrations. Notably, AV5116 was equipotent or more potent than baloxavir acid (BXA) against WT (I38-WT) viruses and viruses with reduced BXA susceptibility carrying an I38T polymerase acidic (PA) substitution. AV5116 exhibited low cytotoxicity in Madin\u2013Darby canine kidney cells and lacked mitochondrial toxicity, resulting in favourable selective indices. Treatment with 20 or 50\u2009mg\/kg AV5124 prevented death in 60% and 100% of animals, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Overall, AV5124 and A5116 are promising inhibitors of the influenza virus CEN and warrant further development as potent anti-influenza agents.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkaa524","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T12:09:56Z","timestamp":1606997396000},"page":"1010-1018","source":"Crossref","is-referenced-by-count":16,"title":["Synthesis, inhibitory activity and oral dosing formulation of AV5124, the structural analogue of influenza virus endonuclease inhibitor baloxavir"],"prefix":"10.1093","volume":"76","author":[{"given":"Andrei A","family":"Ivashchenko","sequence":"first","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"},{"name":"ChemDiv, 12760 High Bluff Drive, Ste. 370 San Diego, CA 92130, USA"},{"name":"Moscow Institute of Physics and Technology (State University), Institutskiy Lane, Dolgoprudny, Moscow Region 141700, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg D","family":"Mitkin","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy C","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V","family":"Nikitin","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela G","family":"Koryakova","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben N","family":"Karapetian","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry V","family":"Kravchenko","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan V","family":"Mochalov","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey A","family":"Ryakhovskiy","sequence":"additional","affiliation":[{"name":"Chemical Diversity Research Institute, Rabochaya St. 2a, Khimki, Moscow Region 141401, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Aladinskiy","sequence":"additional","affiliation":[{"name":"Moscow Institute of Physics and Technology (State University), Institutskiy Lane, Dolgoprudny, Moscow Region 141700, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina A","family":"Leneva","sequence":"additional","affiliation":[{"name":"I. Mechnikov Research Institute for Vaccines and Sera, 5a Malyy Kazennyy lane, Moscow 105064, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina N","family":"Falynskova","sequence":"additional","affiliation":[{"name":"I. Mechnikov Research Institute for Vaccines and Sera, 5a Malyy Kazennyy lane, Moscow 105064, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina A","family":"Glubokova","sequence":"additional","affiliation":[{"name":"I. 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