To hit or not to hit: Large-scale sequence analysis and structure characterization of influenza A NS1 unlocks new antiviral target potential.

Autor: Trigueiro-Louro JM; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016, Lisbon, Portugal. Electronic address: joao.louro@insa.min-saude.pt., Correia V; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016, Lisbon, Portugal., Santos LA; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016, Lisbon, Portugal., Guedes RC; Medicinal Chemistry Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal., Brito RMM; Chemistry Department and Coimbra Chemistry Centre, Faculty of Science and Technology, University of Coimbra, 3004-535, Coimbra, Portugal., Rebelo-de-Andrade H; Host-Pathogen Interaction Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal; Antiviral Resistance Lab, Research & Development Unit, Infectious Diseases Department, Instituto Nacional de Saúde Doutor Ricardo Jorge, IP, Av. Padre Cruz, 1649-016, Lisbon, Portugal. Electronic address: H.Rebelo.Andrade@insa.min-saude.pt.
Jazyk: angličtina
Zdroj: Virology [Virology] 2019 Sep; Vol. 535, pp. 297-307. Date of Electronic Publication: 2019 Apr 27.
DOI: 10.1016/j.virol.2019.04.009
Abstrakt: Influenza NS1 protein is among the most promising novel druggable anti-influenza target, based on its structure; multiple interactions; and global function in influenza replication and pathogenesis. Notwithstanding, drug development guidance based on NS1 structural biology is lacking. Here, we design a promising strategy directed to highly conserved druggable regions as a result of an exhaustive large-scale sequence analysis and structure characterization of NS1 protein across human-infecting influenza A subtypes, over the past 100 years. We have identified 3 druggable pockets and 8 new potential hot spot residues in the NS1 protein, not described before, additionally to other 16 sites previously identified, which represent attractive targets for pharmacological modulation. This study provides a rationale towards structure-function studies of NS1 druggable sites, which have the potential to accelerate the NS1 target validation. This research also contributes to a deeper comprehension and insight into the evolutionary dynamics of influenza A NS1 protein.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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