Chikungunya virus drug discovery: still a long way to go?

ABSTRACT

Introduction: Chikungunya virus (CHIKV) is the etiological agent of a (re)emerging arbovirus infection, chikungunya fever (CHIKF), that represents a serious health problem worldwide for which no antivirals are available.

Areas covered: This review covers the efforts performed so far to identify and optimize small molecules that could be useful as antivirals for CHIKV infection, including drug repositioning, phenotypic screening, target-based screening, and structure-based design. This is accompanied by a brief presentation of the replicative cycle of the virus and the role of the viral proteins in CHIKV replication.

Expert opinion: In the last decade, and particularly since CHIKV reached the Americas, significant efforts have been made to identify compounds that effectively inhibit CHIKV replication. Unfortunately, these efforts have not led to a clinical candidate. For the years to come, more basic research is required to allow a better understanding of the interplay of the viral proteins among them and with cellular components. Structural information is missing for most of the targets so that structure-based drug design, a strategy that has provided good results in other antiviral fields, has been scarcely applied to this alphavirus.

KEYWORDS:

• Chikungunya virus
• drug repurposing
• phenotypic screening
• structure-based drug design
• target-based assays

ARTICLE HIGHLIGHTS

• CHIKV, a (re)emerging alphavirus transmitted by the bites of infected Aedes mosquitos, has expanded worldwide in tropical and subtropical areas with high morbidity that implies important social and economic consequences.

• Drug discovery strategies against CHIKV have been based on reposition of existing drugs as antivirals or addressing host factors, phenotypic screenings, and to a lesser extent, target-based screenings and structure-based design.

• Despite the efforts performed in the last decade to identify and optimize new inhibitors or to reposition existing drugs, no compound has progressed towards clinical trials.

• Structural studies on CHIKV proteins and their interaction with ligands are required since they constitute a key issue in the identification and optimization of hits.

• Basic research on the interaction among viral proteins and/or with cellular components is mandatory to better establish the functional replicative complex in order to design rational approaches to interfere with these complexes, crucial for viral replication.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

L Delang is funded by a C2 project of KU Leuven (C22-18-007) and a research grant of the Fund for Scientific Research (FWO) Flanders (1522918N). MJ Perez-Perez and EM Priego acknowledge the funding of their own research on this subject through a research grant from Spanish MINECO (SAF2015-64629-C2-1-R)