Targeting Chikungunya Virus Entry: alternatives for new inhibitors in drug discovery.

Chikungunya virus (CHIKV) is an Alphavirus (Togaviridae) responsible for Chikungunya fever (CHIKF) that is mainly characterized by a severe polyarthralgia, in which it is transmitted by the bite of infected Aedes aegypti and Ae. albopictus mosquitoes. Nowadays, there no licensed vaccines or approved drugs to specifically treat this viral disease. Structural viral proteins participate in key steps of its replication cycle, such as viral entry, membrane fusion, nucleocapsid assembly, and virus budding. In this context, envelope E3-E2-E1 glycoproteins complex could be targeted for designing new drug candidates. In this review, aspects of the CHIKV entry process are discussed to provide insights to assist the drug discovery process. Moreover, several natural, nature-based and synthetic compounds, as well as repurposed drugs and virtual screening, are also explored as alternatives for developing CHIKV entry inhibitors. Finally, we provided a complimentary analysis of studies involving inhibitors that were not explored by in silico methods. Based on this, Phe118, Val179, and Lys181 were found to be the most frequent residues, being present in 89.6, 82.7, and 93.1% of complexes, respectively. Lastly, some chemical aspects associated with interactions of these inhibitors and mature envelope E3-E2-E1 glycoproteins' complex were discussed to provide data for scientists worldwide, supporting their search for new inhibitors against this emerging arbovirus.