Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase

Jianmei Chen; Shujun Feng; Yurui Xu; Xinyu Huang; Jikang Zhang; Jiao Chen; Xueying An; Yu Zhang; Xinghai Ning

doi:10.1039/c9md00473d

Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase

RSC Med Chem. 2020 Jan 22;11(1):148-154. doi: 10.1039/c9md00473d. eCollection 2020 Jan 1.

Authors

Jianmei Chen^{1

2}, Shujun Feng^{1

2}, Yurui Xu^{1

2}, Xinyu Huang^{1

2}, Jikang Zhang^{1

2}, Jiao Chen³, Xueying An⁴, Yu Zhang^{1

2}, Xinghai Ning^{1

2}

Affiliations

¹ Department of Biomedical Engineering , Nanjing National Laboratory of Microstructures , College of Engineering and Applied Sciences , Nanjing University , Nanjing , Jiangsu 210093 , China . Email: zhangyu2016@nju.edu.cn ; Email: xning@nju.edu.cn.
² Chemistry and Biomedicine Innovation Center , Nanjing University , China.
³ Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing , Jiangsu 210028 , China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology , Department of Sports Medicine and Adult Reconstructive Surgery , Nanjing Drum Tower Hospital , The Affiliated Hospital of Nanjing University Medical School , 321 Zhongshan Road , Nanjing 210008 , Jiangsu , PR China.

Abstract

Neuraminidase, an abundant glycoprotein on the influenza virus surface, plays crucial roles in virus replication. Targeting neuraminidase could be a splendid way for the prevention of the spread of influenza infections. Herein, we have identified an octapeptide (errKPAQP) from a synthesized peptide library, originating from mimicking the binding pocket of oseltamivir in neuraminidase, as a potent peptide neuraminidase inhibitor. The docking-based virtual studies showed that errKPAQP exhibited a strong binding affinity (a docking score of -20.03) and nanomolar affinity (11 nM) to influenza neuraminidase, and can inhibit neuraminidase activity at a concentration as low as 4.25 μM, leading to effective protection of MDCK cells from influenza virus-induced death and replication. Furthermore, errKPAQP presented low hemolytic activity, minimal cytotoxicity, and good pharmacokinetic characteristics, which are imperative for an anti-influenza drug. Importantly, errKPAQP was capable of reducing influenza virus-induced inflammation, the serious damage to the lung tissues, and mortality rates in infected mice, indicating that it could protect against the lethal challenge of influenza viruses in vivo. Therefore, we have developed a novel neuraminidase peptide inhibitor with advantageous biological properties and high inhibitory activity towards neuraminidase, and it can serve as a promising anti-influenza drug.