Structure-function insights into chikungunya virus capsid protein: Small molecules targeting capsid hydrophobic pocket

Abstract

The crystal structure of chikungunya (CHIKV) virus capsid protease domain has been determined at 2.2Å. Structure reveals a chymotrypsin-like protease fold with a conserved hydrophobic pocket in CHIKV capsid protein (CP) for interaction with the cytoplasmic tail of E2 (cdE2) similar to the capsid protein of other alphaviruses. Molecular contacts between CP-cdE2 were determined by fitting structures of CHIKV CP and cdE2 into the cryo-EM map of Venezuelan equine encephalitis virus (VEEV). Binding of (S)-(+)-Mandelic acid (MDA) and Ethyl 3-aminobenzoate (EAB) to the hydrophobic pocket of CP was evaluated by molecular docking. Surface plasmon resonance (SPR) and fluorescence spectroscopy experiments confirmed MDA and EAB binding to the CP. The binding constants (K) obtained from SPR for MDA and EAB were 1.2 × 10 M and 0.2 × 10 M, respectively. This study adds to the understanding of chikungunya virus structural proteins and may serve as the basis for antiviral development against chikungunya disease.

The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies

“…A recent study reported that the CHIKV capsid is also able to exhibit trans-cleavage properties [111]. In addition, the hydrophobic pocket (containing interacting residues: Val 130, Gly 131, Val 134, Met 135, Trp 245, and Val 250) located on region 3 was found to interact with Pro 404 of the E2 cytoplasmic domain, which is believed to occur during mature particle assembly [102,106,112]. Moreover, dimerization of two capsid protein monomers relies on the interaction of the Tyr 186 residue from one monomer with two Asn residues at positions 188 and 220 from the other monomer, all of which are located on region 3 [102].…”

Advances in structure-assisted antiviral discovery for animal viral diseases

“…It was found that small molecules such as (S)-(1)-mandelic acid and ethyl 3-aminobenzoate target capsid hydrophobic pocket. These bind to the conserved hydrophobic pocket of CP (Sharma et al, 2018). This may serve as a basis for the development of antivirals against CHIKV infections.…”

Identification of Chikungunya virus nucleocapsid core assembly modulators

“…The capsid protein from CHIK 181/25 (58) was cloned into the pET29 vector and expressed in Rosetta2pRARE2 cells as done previously for other alphavirus capsid proteins (17,18,48,54,59). For ease of purification, we included a 6-His tag at the N-terminus prior to the first amino acid.…”

“…interaction (17)(18)(19). Like Sharma et al saw with CHIKV and picolic, we observed the best inhibition when 4BSA and virus were added simultaneously.…”

“…This expansion is due in part to a mutation in a viral protein, which supportstransmission of the virus in both the Aedes aegypti and Aedes albopictus mosquito vectors (7). A number of inhibitors of CHIKV have been identified including compounds that target the virus lifecycle including genome replication, viral protein synthesis, and virus egress, specifically the interaction of the core with the viral spikes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). These compounds, however, are effective only at high concentrations or resistance is easily acquired.…”