title: Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance.
abstract: As the number of drug-resistant influenza viruses continues to increase, antivirals with novel mechanisms of action are urgently needed. Among the two classes of FDA-approved antiviral drugs, neuraminidase (NA) inhibitors, oseltamivir, zanamivir, and peramivir, are currently the only choice for the prevention and treatment of influenza virus infection. Due to the antigenic drift and antigenic shift, it will only be a matter of time before influenza viruses become completely resistant to these NA inhibitors. In pursuing the next generation of antiviral drugs with complementary mechanisms of action to those of the NA inhibitors, we have identified a natural product, cyclosporine A (CsA) (1), as a desired drug candidate. In this study, we discovered that CsA (1) and its analogs have broad-spectrum antiviral activity against multiple influenza A and B strains, including strains that are resistant to either NA or M2 inhibitors or both. Moreover, CsA (1) displays a high in vitro genetic barrier of drug resistance than oseltamivir carboxylate Mechanistic studies revealed that CsA (1) acts at the intermediate step of viral replication post viral fusion. Its antiviral mechanism is independent of inhibiting the isomerase activity of cyclophilin A (CypA), and CsA (1) has no effect on the viral polymerase activity The potent antiviral efficacy of CsA (1), coupled with the high in vitro genetic barrier of drug resistance and novel mechanism of action, renders CsA (1) a promising anti-influenza drug candidate for further development.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States; BIO5 Institute, The University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States; BIO5 Institute, The University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Rami Ghassan
authors.initials: RG
authors.lastname: Musharrafieh
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States; BIO5 Institute, The University of Arizona, Tucson, AZ 85721, United States. Electronic address: junwang@pharmacy.arizona.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D024882:Drug Resistance, Viral; D016679:Genome, Viral; D005838:Genotype; D006801:Humans; D009980:Influenza A virus / Q000145:classification / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D009981:Influenza B virus / Q000145:classification / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016572:Cyclosporine
keywords: Antiviral; Broad spectrum; CsA; Influenza virus; Resistance; Serial passage