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Screening and identification of inhibitors against influenza A virus from a US drug collection of 1280 drugs.

Antiviral research (2014-06-28)
Liwei An, Rui Liu, Wei Tang, Jian-Guo Wu, Xulin Chen
ABSTRACT

Infection with influenza A virus is still a global concern since it causes significant mortality, morbidity and economic loss. New burst pandemics and rapid emergence of drug-resistance strains in recent years call for novel antiviral therapies. One promising way to overcome this problem is searching new inhibitors among thousands of drugs approved in the clinic for the treatment of different diseases or approved to be safe by clinical trials. In the present work, a collection of 1280 compounds, most of which have been clinically used in human or animal, were screened for anti-influenza activity and 41 hits (SI>4.0) were obtained. Next the 18 hit compounds with SI >10.0 were tested for antiviral activity against 7 other influenza virus strains in canine-originated MDCK cells, 9 compounds exhibited broad antiviral spectrum. The antiviral effects of the 9 compounds were also confirmed in human-originated A549 cells and chicken-originated DF1 cells, by infectious virus yield reduction assay and indirect immunofluorescent assay. Results from the time of addition assay showed that the 9 candidates impaired different stages of influenza virus life cycle, indicating they are novel inhibitors with different mechanisms compared with the existing M2 ion-channel blockers or neuraminidase (NA) inhibitors. Taken together, our findings provide 9 novel drug candidates for the treatment of influenza virus infection. Further mechanism of action study of these inhibitors may lead to the discovery of new anti-influenza targets and structure-activity relationship (SAR) study can be initiated to improve the efficacy of these new classes of influenza inhibitors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ribavirin, antiviral
Sigma-Aldrich
2′-(4-Methylumbelliferyl)-α-D-N-acetylneuraminic acid sodium salt hydrate, ≥95% (HPLC)
Supelco
Betamethasone, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Imazalil, PESTANAL®, analytical standard
Sigma-Aldrich
Betamethasone, ≥98%
Supelco
Betamethasone, VETRANAL®, analytical standard
Betamethasone, European Pharmacopoeia (EP) Reference Standard
USP
Betamethasone, United States Pharmacopeia (USP) Reference Standard
Enilconazole, European Pharmacopoeia (EP) Reference Standard
Ribavirin, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Betamethasone, meets USP testing specifications