tetano
Editor, Senior Moderator
Mol Pharm. 2018 Aug 13. doi: 10.1021/acs.molpharmaceut.8b00531. [Epub ahead of print]
[h=1]A small-molecule compound has anti-influenza A virus activity by acting as a ''PB2 inhibitor".[/h] Liu T, Liu M, Chen F, Chen F, Tian Y, Huang Q, Liu SW, Yang J.
[h=3]Abstract[/h] With regular influenza epidemics and the emergence of drug-resistant virus strains, it is extremely crucial to develop effective and low-toxicity anti-influenza A virus drugs that act on conserved sites of novel targets. Here, we identified a novel anti-influenza compound, 1,3-dihydroxy-6-benzo [c] chromene (D715-2441), from a library of 8,026 small molecule compounds using cell-based influenza A infection assays and explored the underlying mechanisms. Our results revealed that D715-2441 possessed antiviral activities against multiple subtypes of influenza A viruses, including H1N1, H3N2, H5N1, H7N9, the clinical isolate 690 (H3 subtype) and oseltamivir-resistant strains with an NA-H274Y mutation, and suppressed the early steps in the virus replication cycle. Further mechanistic studies indicated that D715-2441 clearly inhibited viral polymerase activity and directly influenced the location of the PB2 protein. Moreover, binding affinity analyses confirmed that D715-2441 bound specifically to the PB2cap protein. Significantly, a computer-aided molecular docking and protein sequence alignment indicated that highly conserved residues in the cap-binding domain (residues 318-483) of PB2cap might be the possible binding site of D715-2441, which indicates that D715-2441 might be able to be employed as a cap-binding competitor. Moreover, the combination of D715-2441 and zanamivir possessed a remarkable synergistic antiviral effect, with a FICI value of 0.40. In conclusion, these results strongly suggest that D715-2441 has potential as a promising candidate against IAV infection. More importantly, our study offers new options for the strategic development of cap-binding inhibitors of influenza A viruses.
PMID: 30102858 DOI: 10.1021/acs.molpharmaceut.8b00531
[h=1]A small-molecule compound has anti-influenza A virus activity by acting as a ''PB2 inhibitor".[/h] Liu T, Liu M, Chen F, Chen F, Tian Y, Huang Q, Liu SW, Yang J.
[h=3]Abstract[/h] With regular influenza epidemics and the emergence of drug-resistant virus strains, it is extremely crucial to develop effective and low-toxicity anti-influenza A virus drugs that act on conserved sites of novel targets. Here, we identified a novel anti-influenza compound, 1,3-dihydroxy-6-benzo [c] chromene (D715-2441), from a library of 8,026 small molecule compounds using cell-based influenza A infection assays and explored the underlying mechanisms. Our results revealed that D715-2441 possessed antiviral activities against multiple subtypes of influenza A viruses, including H1N1, H3N2, H5N1, H7N9, the clinical isolate 690 (H3 subtype) and oseltamivir-resistant strains with an NA-H274Y mutation, and suppressed the early steps in the virus replication cycle. Further mechanistic studies indicated that D715-2441 clearly inhibited viral polymerase activity and directly influenced the location of the PB2 protein. Moreover, binding affinity analyses confirmed that D715-2441 bound specifically to the PB2cap protein. Significantly, a computer-aided molecular docking and protein sequence alignment indicated that highly conserved residues in the cap-binding domain (residues 318-483) of PB2cap might be the possible binding site of D715-2441, which indicates that D715-2441 might be able to be employed as a cap-binding competitor. Moreover, the combination of D715-2441 and zanamivir possessed a remarkable synergistic antiviral effect, with a FICI value of 0.40. In conclusion, these results strongly suggest that D715-2441 has potential as a promising candidate against IAV infection. More importantly, our study offers new options for the strategic development of cap-binding inhibitors of influenza A viruses.
PMID: 30102858 DOI: 10.1021/acs.molpharmaceut.8b00531