tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Feb 6;250:115185.
doi: 10.1016/j.ejmech.2023.115185. Online ahead of print.
Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit
Sihan Wang[SUP] 1 [/SUP], Zhimin Ying[SUP] 2 [/SUP], Youchun Huang[SUP] 2 [/SUP], Yuting Li[SUP] 1 [/SUP], Menglong Hu[SUP] 1 [/SUP], Ke Kang[SUP] 2 [/SUP], Haiyang Wang[SUP] 2 [/SUP], Jiaan Shao[SUP] 3 [/SUP], Gaoqi Wu[SUP] 4 [/SUP], Yongping Yu[SUP] 2 [/SUP], Yushen Du[SUP] 5 [/SUP], Wenteng Chen[SUP] 6 [/SUP]
Affiliations
Abstract
The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-β[SUP]3[/SUP]- or β[SUP]2,3[/SUP] -amino acids were synthesized possessing a good binding affinity of PB2. The aza-β-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated. Then a lead HAA-09 was validated, and the attached aza-β[SUP]3[/SUP]-amino acid moiety with acyclic tertiary carbon side chain well occupied in the key hydrophobic cavity of PB2_cap binding domain. Importantly, HAA-09 displays potent polymerase inhibition capacity, low cytotoxicity (selectivity index up to 2915) as well as robust anti-viral activity against A/WSN/33 (H1N1) virus and oseltamivir-resistant H275Y variant. Moreover, HAA-09 exhibited druggability with high plasma stability (t[SUB]1/2[/SUB] ≥ 12 h) and no obvious hERG inhibition (IC[SUB]50[/SUB] > 10 μM). Also, HAA-09 demonstrated a favorable safety profile when orally administrated in healthy mice at a high dose of 40 mg/kg QD for consecutive 3 days. Besides, in vivo therapeutic efficacy (85.7% survival observed at the day 15 post infection) was demonstrated when HAA-09 was administrated orally at 12.5 mg/kg BID starting 48 h post infection for 9 days. These data support that exploring the interactions between side chains on aza-β[SUP]3[/SUP]- or β[SUP]2,3[/SUP] -amino acid moieties and hydrophobic pocket of PB2_cap binding domain is a potential medicinal chemistry strategy for developing potent PB2 inhibitors.
Keywords: Anti-Influenza; Aza-β-amino acids; PB2 subunit; SAR optimization; Side chain diversity.
. 2023 Feb 6;250:115185.
doi: 10.1016/j.ejmech.2023.115185. Online ahead of print.
Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit
Sihan Wang[SUP] 1 [/SUP], Zhimin Ying[SUP] 2 [/SUP], Youchun Huang[SUP] 2 [/SUP], Yuting Li[SUP] 1 [/SUP], Menglong Hu[SUP] 1 [/SUP], Ke Kang[SUP] 2 [/SUP], Haiyang Wang[SUP] 2 [/SUP], Jiaan Shao[SUP] 3 [/SUP], Gaoqi Wu[SUP] 4 [/SUP], Yongping Yu[SUP] 2 [/SUP], Yushen Du[SUP] 5 [/SUP], Wenteng Chen[SUP] 6 [/SUP]
Affiliations
- PMID: 36773549
- DOI: 10.1016/j.ejmech.2023.115185
Abstract
The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-β[SUP]3[/SUP]- or β[SUP]2,3[/SUP] -amino acids were synthesized possessing a good binding affinity of PB2. The aza-β-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated. Then a lead HAA-09 was validated, and the attached aza-β[SUP]3[/SUP]-amino acid moiety with acyclic tertiary carbon side chain well occupied in the key hydrophobic cavity of PB2_cap binding domain. Importantly, HAA-09 displays potent polymerase inhibition capacity, low cytotoxicity (selectivity index up to 2915) as well as robust anti-viral activity against A/WSN/33 (H1N1) virus and oseltamivir-resistant H275Y variant. Moreover, HAA-09 exhibited druggability with high plasma stability (t[SUB]1/2[/SUB] ≥ 12 h) and no obvious hERG inhibition (IC[SUB]50[/SUB] > 10 μM). Also, HAA-09 demonstrated a favorable safety profile when orally administrated in healthy mice at a high dose of 40 mg/kg QD for consecutive 3 days. Besides, in vivo therapeutic efficacy (85.7% survival observed at the day 15 post infection) was demonstrated when HAA-09 was administrated orally at 12.5 mg/kg BID starting 48 h post infection for 9 days. These data support that exploring the interactions between side chains on aza-β[SUP]3[/SUP]- or β[SUP]2,3[/SUP] -amino acid moieties and hydrophobic pocket of PB2_cap binding domain is a potential medicinal chemistry strategy for developing potent PB2 inhibitors.
Keywords: Anti-Influenza; Aza-β-amino acids; PB2 subunit; SAR optimization; Side chain diversity.