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.

Targeting the nsp2 Cysteine Protease of Chikungunya Virus Using FDA Approved Library and Selected Cysteine Protease Inhibitors

“…Another cysteine protease inhibitor, Leupeptin hemisulfate, has also shown significant docking score (−7.08 kcal/mol) and binding energy (−44.461 kcal/mol) and it is interacting with Trp1084 via hydrogen bond along with Q1241 and D1246 residue. It also inhibits a wide range of enzymes like cathepsin, calpain, trypsin, etc., with significant Ki values [28,38]. Mostly, compounds are interacting with conserved residues through hydrogen bonding or other non-covalent interactions such as salt bridge formation, pi-pi stacking and pi-cation bonds with Asp1082, Trp1084, Lys1091 and Arg1271 residues (Table 2).…”

“…Nowadays, computational approaches have emerged on a large scale to help researchers in finding novel drugs and vaccine against a particular target in less time and cost. In addition, the “drug repurposing” or “drug repositioning” approach is quite useful to find out active molecules against different targets where most of the safety parameters were already reported for these molecules [28]. Here, in our study we have also virtually screened drugs approved by Food and Drug Administration (FDA), USA against nsp2 protease of chikungunya virus.…”

Plant-Based Natural Products and Extracts: Potential Source to Develop New Antiviral Drug Candidates

“…However, there are many proteins involved in the CHIKV replication cycle that have no structural information. There has been extensive screening for activating anti-CHIKV natural products; while most only show moderate activity, they may serve as lead compounds for developing helpful therapeutics [ 90 ]. There is an obvious need for discovery in preventative and curing treatments for these and other viruses, which is a need that may be satisfied through natural sources.…”

Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery

“…CHIKV infections are characterized by high fever, fatigue, joint and muscle pains, with serious long-term effects including debilitating polyarthralgia 6 , 7 . Despite its medical importance, no vaccines or antivirals against any alphavirus is currently available 8 , 9 .…”