Inhibition of chikungunya virus by picolinate that targets viral capsid protein.
The protein-protein interactions (PPIs) of the transmembrane glycoprotein E2 with the hydrophobic pocket on the surface of capsid protein (CP) plays a critical role in alphavirus life cycle. Dioxane based derivatives targeting PPIs have been reported to possess antiviral activity against Sindbis Virus (SINV), the prototype alphavirus. In this study, the binding of picolinic acid (PCA) to the conserved hydrophobic pocket of capsid protein was analyzed by molecular docking, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR) and fluorescence spectroscopy. The binding constant KD obtained for PCA was 2.1×10(-7)M. Additionally, PCA significantly inhibited CHIKV replication in infected Vero cells, decreasing viral mRNA and viral load as assessed by qRT-PCR and plaque reduction assay, respectively. This study is suggestive of the potential of pyridine ring compounds as antivirals against alphaviruses and may serve as the basis for the development of PCA based drugs against alphaviral diseases.
Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India.
Rajesh
R
Sharma
Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India.
Benazir
B
Fatma
Division of Virology, Defence Research and Development Establishment, Gwalior 474002, India.
Amrita
A
Saha
GE Healthcare Life Sciences, John F Welch Technology Centre, EPIP, Phase 2, Whitefield Road, Bangalore 560048, India.
Sailesh
S
Bajpai
GE Healthcare Life Sciences, John F Welch Technology Centre, EPIP, Phase 2, Whitefield Road, Bangalore 560048, India.
Srinivas
S
Sistla
Division of Virology, Defence Research and Development Establishment, Gwalior 474002, India.
Paban Kumar
PK
Dash
Division of Virology, Defence Research and Development Establishment, Gwalior 474002, India.
Manmohan
M
Parida
Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India.
Pravindra
P
Kumar
Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee 247667, India. Electronic address: shailfbt@iitr.ac.in.
Shailly
S
Tomar
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D002646:Chikungunya virus / Q000187:drug effects* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D020349:Surface Plasmon Resonance
D000998:Antiviral Agents; D036022:Capsid Proteins; D010848:Picolinic Acids; D011994:Recombinant Proteins; C030614:picolinic acid
Antiviral; Capsid protein; Chikungunya virus; Picolinic acid; Protein-protein interactions; Pyridine ring, Surface Plasmon resonance; Quantitative real-time RT-PCR