2. Academic Validation
  3. Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit

Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit

  • Eur J Med Chem. 2023 Mar 15;250:115185. doi: 10.1016/j.ejmech.2023.115185.
Sihan Wang 1,  Zhimin Ying 2,  Youchun Huang 2,  Yuting Li 1,  Menglong Hu 1,  Ke Kang 2,  Haiyang Wang 2,  Jiaan Shao 3,  Gaoqi Wu 4,  Yongping Yu 2,  Yushen Du 5,  Wenteng Chen 6
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
  • 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
  • 3 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, PR China.
  • 4 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 5 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang University, Hangzhou, Zhejiang, 310003, China. Electronic address: lilyduyushen@zju.edu.cn.
  • 6 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China. Electronic address: wentengchen@zju.edu.cn.
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-β3- or β2,3 -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-β3-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 (t1/2 ≥ 12 h) and no obvious hERG inhibition (IC50 > 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-β3- or β2,3 -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.

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