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Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase.

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 ?M, 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.

SUBMITTER: Chen J

PROVIDER: S-EPMC7433756 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase.

Chen Jianmei J Feng Shujun S Xu Yurui Y Huang Xinyu X Zhang Jikang J Chen Jiao J An Xueying X Zhang Yu Y Ning Xinghai X

RSC medicinal chemistry 20200122 1

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 ...[more]

PMID: 33479615

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Project description:Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 microg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants.

Project description:With the recent introduction of neuraminidase (NA) inhibitors into clinical practice for the treatment of influenza virus infections, considerable attention has been focused on the potential for resistance development and cross-resistance between different agents from this class. A-315675 is a novel influenza virus NA inhibitor that has potent enzyme activity and is highly active in cell culture against a variety of strains of influenza A and B viruses. To further assess the therapeutic potential of this compound, in vitro resistance studies have been conducted and a comparative assessment has been made relative to oseltamivir carboxylate. The development of viral resistance to A-315675 was studied by in vitro serial passage of influenza A/N9 virus strains grown in MDCK cells in the presence of increasing concentrations of A-315675. Parallel passaging experiments were conducted with oseltamivir carboxylate, the active form of a currently marketed oral agent for the treatment of influenza virus infections. Passage experiments with A-315675 identified a variant at passage 8 that was 60-fold less susceptible to the compound. Sequencing of the viral population identified an E119D mutation in the NA gene, but no mutations were observed in the hemagglutinin (HA) gene. However, by passage 10 (2.56 microM A-315675), two mutations (R233K, S339P) in the HA gene appeared in addition to the E119D mutation in the NA gene, resulting in a 310-fold-lower susceptibility to A-315675. Further passaging at higher drug concentrations had no effect on the generation of further NA or HA mutations (20.5 microM A-315675). This P15 virus displayed 355-fold-lower susceptibility to A-315675 and >175-fold-lower susceptibility to zanamivir than did wild-type virus, but it retained a high degree of susceptibility to oseltamivir carboxylate. By comparison, virus variants recovered from passaging against oseltamivir carboxylate (passage 14) harbored an E119V mutation and displayed a 6,000-fold-lower susceptibility to oseltamivir carboxylate and a 175-fold-lower susceptibility to zanamivir than did wild-type virus. Interestingly, this mutant still retained susceptibility to A-315675 (42-fold loss). This suggests that cross-resistance between A-315675- and oseltamivir carboxylate-selected variants in vitro is minimal.

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Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase.

Publications

Discovery and characterization of a novel peptide inhibitor against influenza neuraminidase.

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