2. Academic Validation
  3. Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics

Optimization and biological evaluation of l-DOPA derivatives as potent influenza PAN endonuclease inhibitors with multi-site binding characteristics

  • Bioorg Chem. 2024 Jan 19:144:107139. doi: 10.1016/j.bioorg.2024.107139.
Jiaai Ruan 1,  Kunyu Lu 2,  Jianfu He 2,  Yihao Chen 1,  Baixi Li 1,  Xin Wan 3,  Xiao Chen 1,  Sumei Li 4,  Shuwen Liu 5,  Gaopeng Song 6
Affiliations

Affiliations

  • 1 Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Huizhou Health Sciences Polytechnic, Huizhou 516025, China.
  • 4 Department of Human Anatomy, College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou 510632, China. Electronic address: lisumei1234@163.com.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China. Electronic address: liusw@smu.edu.cn.
  • 6 Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China. Electronic address: songgp1021@scau.edu.cn.
PMID: 38262086 DOI: 10.1016/j.bioorg.2024.107139
Abstract

Emerging and potential influenza pandemics still are an enormous worldwide public health challenge. The PAN 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 PAN 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 PAN Endonuclease Inhibitor and Antiviral agent. The lead T-31 inhibited PAN Endonuclease activity with an IC50 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 PAN 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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z