In silico structure-based design of enhanced peptide inhibitors targeting RNA polymerase PAN-PB1C interaction

Arundhathi Arivajiagane; Narendrakumar Ravi Varadharajulu; Kumar Seerangan; Rajesh Rattinam

doi:10.1016/j.compbiolchem.2018.12.009

In silico structure-based design of enhanced peptide inhibitors targeting RNA polymerase PA_N-PB1_C interaction

Comput Biol Chem. 2019 Feb:78:273-281. doi: 10.1016/j.compbiolchem.2018.12.009. Epub 2018 Dec 23.

Authors

Arundhathi Arivajiagane¹, Narendrakumar Ravi Varadharajulu², Kumar Seerangan³, Rajesh Rattinam⁴

Affiliations

¹ Department of Biotechnology, University of Madras, Guindy Campus, Chennai, 600 025, India; Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, No. 75 Bo-Ai Street, Hsinchu, 300, Taiwan.
² Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan.
³ Department of Agro-Food System (Agrisystem), Università Cattolica del Sacro Cuore Piacenza-Cremona, 29122 Piacenza Via Emilia Parmense, 84, Italy.
⁴ Department of Microbial Biotechnology, Bharathiyar University, Coimbatore, 641046, India. Electronic address: rajeshbuibt@gmail.com.

PMID: 30597438
DOI: 10.1016/j.compbiolchem.2018.12.009

Abstract

Developing antivirals for influenza A virus (FluA) has become more challenging due to high range of antigenic mutation and increasing numbers of drug-resistant viruses. Finding a selective inhibitor to target highly conserved region of protein-protein interactions interface, thereby increasing its efficiency against drug resistant virus could be highly beneficial. In this study, we used in silico approach to derive FluAPep1 from highly conserved region, PA_N-PB1_C interface and generated 121 FluAPep1 analogues. Interestingly, we found that the FluAPep1 interaction region in the PA_N domain are highly conserved in many FluA subtypes. Especially, FluAPep1 targets two pandemic FluA strains, H1N1/avian/2009 and H3N2/Victoria/1975. All of these FluA subtypes PA_N domain (H1N1/H3N2CAN/H3N2VIC/H7N1/H7N2) were superimposed with PA_N domain from H17N10 and the calculated root mean standards deviations were less than 3 Å. FlexPepDock analysis revealed that FluAPep1 exhibited higher binding affinity (score -246.155) with the PA_N domain. In addition, around 86% of non-hot spot mutated peptides (FluAPep28-122) showed enhanced binding affinity with PA_N domain. ToxinPred analysis confirmed that designed peptides were non-toxic. Thus, FluAPep1 and its analogues has potential to be further developed into an antiviral treatment against FluA infection.

Keywords: FluAPep1; Influenza A virus; PA(N) domain; Protein-protein interactions; RNA polymerase.

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Computer Simulation*
DNA-Directed RNA Polymerases / chemistry
DNA-Directed RNA Polymerases / metabolism*
Drug Design*
Humans
Influenza A virus / drug effects
Influenza A virus / enzymology
Influenza A virus / metabolism
Influenza, Human / drug therapy*
Influenza, Human / virology
Microbial Sensitivity Tests
Molecular Structure
Peptides / chemistry
Peptides / metabolism*
Protein Binding / drug effects

Substances

Antiviral Agents
Peptides
DNA-Directed RNA Polymerases