Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections.

Ana-Belén Blázquez,Juan-Carlos Saiz

doi:10.3390/ijms21249524

Abstract

Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.

Highlights

Kinases are a group of enzymes that catalyze the transfer of the terminal γ-phosphate from ATP to the hydroxyl group of an acceptor substrate, participating in a huge variety of cellular processes, such as proliferation, apoptosis, metabolism, transcription, or antibiotic resistance, among others
AGC kinase group is named for the initials of its members, kinases related to cAMP-dependent protein kinase 1 (PKA), cGMP-dependent protein kinase (PKG), and protein kinase C (PKC)
Two different approaches are being applied in the quest for antivirals: DAAs, directly aimed to viral targets, or HDAs that target cellular components essential for the viral life cycle

Summary

Introduction

Kinases are a group of enzymes that catalyze the transfer of the terminal γ-phosphate from ATP to the hydroxyl group of an acceptor substrate, participating in a huge variety of cellular processes, such as proliferation, apoptosis, metabolism, transcription, or antibiotic resistance, among others. Kinases are a key target for therapies against microbial and viral diseases [18,19] In this sense, viral infections rely on virus–host interactions, and it has been described that host cell kinases play crucial roles in every step of the viral life cycle in a wide range of viral species, including members of the Flaviviridae family (flaviviruses and hepaciviruses) [19,20,21,22]. Src-family kinase (SFK) inhibitors were reported to block DENV infection by altering virus assembly and secretion [69], and modulation of CAMKII activity impacted attachment of JEV to the host cell surface and viral entry [70]. PKA activity affected ZIKV replication at the post-entry stage by affecting negative-sense RNA synthesis, and HCV infection induces PKA activation to enhance virus entry and infectivity [71]

Protein Kinase Targets in the Control of Virus of the Flaviviridae Family

The AGC Kinase

CMGC Kinases

Other PKs

Findings

Conclusions