tetano
Editor, Senior Moderator
Bioorg Chem
. 2024 Jan 19:144:107139.
doi: 10.1016/j.bioorg.2024.107139. Online ahead of print. Optimization and biological evaluation of l-DOPA derivatives as potent influenza PA[SUB]N[/SUB] endonuclease inhibitors with multi-site binding characteristics
Jiaai Ruan[SUP] 1 [/SUP], Kunyu Lu[SUP] 2 [/SUP], Jianfu He[SUP] 2 [/SUP], Yihao Chen[SUP] 1 [/SUP], Baixi Li[SUP] 1 [/SUP], Xin Wan[SUP] 3 [/SUP], Xiao Chen[SUP] 1 [/SUP], Sumei Li[SUP] 4 [/SUP], Shuwen Liu[SUP] 5 [/SUP], Gaopeng Song[SUP] 6 [/SUP]
Affiliations
Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PA[SUB]N[/SUB] endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PA[SUB]N[/SUB] inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PA[SUB]N[/SUB] endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PA[SUB]N[/SUB] endonuclease activity with an IC[SUB]50[/SUB] value of 0.15 μM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PA[SUB]N[/SUB] endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.
Keywords: Influenza A virus; PA(N) endonuclease inhibitors; Structure–activity relationship; l-DOPA derivatives.
. 2024 Jan 19:144:107139.
doi: 10.1016/j.bioorg.2024.107139. Online ahead of print. Optimization and biological evaluation of l-DOPA derivatives as potent influenza PA[SUB]N[/SUB] endonuclease inhibitors with multi-site binding characteristics
Jiaai Ruan[SUP] 1 [/SUP], Kunyu Lu[SUP] 2 [/SUP], Jianfu He[SUP] 2 [/SUP], Yihao Chen[SUP] 1 [/SUP], Baixi Li[SUP] 1 [/SUP], Xin Wan[SUP] 3 [/SUP], Xiao Chen[SUP] 1 [/SUP], Sumei Li[SUP] 4 [/SUP], Shuwen Liu[SUP] 5 [/SUP], Gaopeng Song[SUP] 6 [/SUP]
Affiliations
- PMID: 38262086
- DOI: 10.1016/j.bioorg.2024.107139
Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PA[SUB]N[/SUB] endonuclease has been proved to be a promising target for anti-influenza drug design. Here, we report the discovery and optimization of potent Y-shaped PA[SUB]N[/SUB] inhibitors featuring multi-site binding characteristics with l-DOPA as a starting point. We systematically modified the hit 1 bearing two-binding characteristics based on structure-based rational design combined with multisite binding and conformational constraint strategies, generating four families of l-DOPA derivatives for SARs analysis. Among these substances, N, 3-di-substituted 1, 2, 3, 4-tetrahydroisoquinoline derivative T-31 displayed superior properties as a lead PA[SUB]N[/SUB] endonuclease inhibitor and antiviral agent. The lead T-31 inhibited PA[SUB]N[/SUB] endonuclease activity with an IC[SUB]50[/SUB] value of 0.15 μM and showed broad and submicromolar anti-influenza potency in cell-based assays. More importantly, T-31 could simultaneously target both influenza HA and the RdRp complex, thus interfering with virus entry into host cells and viral replication. This study offers a set of novel PA[SUB]N[/SUB] endonuclease inhibitors with multi-site binding characteristics starting from the l-DOPA skeleton.
Keywords: Influenza A virus; PA(N) endonuclease inhibitors; Structure–activity relationship; l-DOPA derivatives.