Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Abstract

Infections with flaviviruses, such as dengue, West Nile virus, and the recently re-emerging Zika virus are an increasing and probably lasting global risk. This review summarizes and comments on the opportunities for broad-spectrum agents that are active against a range of flaviviruses. Broad-spectrum activity would be particularly desirable as preparatory measure for the next flaviviral epidemic that could emerge from as-yet-unknown or neglected viruses. Potential target sites for broad-spectrum anti-flaviviral compounds include viral proteins and host mechanisms that are exploited by these viruses during entry and replication. A variety of compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For some other compound classes, broad-spectrum activity can be anticipated because of their mode of action and molecular target(s).

RNA‐virus proteases counteracting host innate immunity

“…The proteases of emerging or re‐emerging (+)ssRNA viruses are always worth investigating, either as targets for direct antivirals disrupting polyprotein processing or as important players in mounting the viral anti‐IFN activity. In this review, we discussed the roles of viral proteases from the families Picornaviridae, Coronaviridae, and Flaviviridae in counteracting host innate immune responses.…”

“…Currently, no approved drug is available that targets the flavivirus NS2B/NS3 pro . Several peptide aldehydes and peptide boronic‐acid inhibitors have been described to inhibit the activity of the flavivirus NS2B/NS3 pro .…”

Identification of Broad‐Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6‐Diaminopurine Scaffolds

“…However, they may provide useful indications on which scaffolds could be further pursued in lead optimization studies (e.g., purine and quinoline scaffolds). At the same time, ex novo targeted approaches against host or viral proteins have been pursued to develop new drug candidates with broad‐spectrum activity against flaviviruses . Among the different approaches, the NS5 polymerase still represents the most promising and exploited target for the development of broad‐spectrum anti‐flaviviral agents.…”

“…In summary, exploration of the chemical space around two chemical scaffolds previously identified by us (quinoline and 2,6‐diaminopurine) allowed conversion of the multitarget inhibitor of DENV replication and Src/Fyn kinases ( 1 ) into novel inhibitors ( 12 a and 12 b ) with broad‐spectrum anti‐flavivirus activity and no significant adverse effect on the activity of a mini‐panel of host kinases. Although the pharmacological and antiviral profile is still unsuitable for evaluation in in vivo studies, compounds 12 a and 12 b can be regarded as among the few non‐nucleoside, broad‐spectrum flavivirus inhibitors reported so far . Because these compounds are inexpensive to produce and easy to functionalize, they are a promising starting point for optimizing their pharmacological profile.…”

A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses

“…For both CHIKV and DENV, there are no approved therapeutics aside from palliative care and pain reduction (Fischer et al, 2014; Lee et al, 2017), although many direct virus targeting compounds have been investigated (Boldescu et al, 2017; Powers, 2018). Due to a potent innate immune response and sterilizing immunity, the acute phase of CHIKV and DENV infection is relatively short compared to the duration of chronic infection by other viruses, such as HIV or hepatitis C virus, so the risk of developing escape mutants to a given antiviral compound is lessened.…”