Chikungunya virus (CHIKV) is a mosquito-borne alphavirus, which poses a significant health threat as seen by recent outbreaks driven by the spread of the mosquito vectors to new geographical areas.
The CHIKV nsP3 macrodomain functions as an ADP-ribosyl (ADPr) hydrolase, counteracting the innate immune response. It is highly conserved between alphaviruses and deficiency in the ADPr-binding and hydrolase function of the nsP3 macrodomain was shown to attenuate CHIKV virulence in mice and to lead to reduced viral replication in cell culture, making it an attractive target for antiviral research.
We have previously performed a high-throughput, crystallographic fragment screen on the nsP3 macrodomain of CHIKV, screening a total of 1385 fragments yielding 109 fragment hits covering the ADPr-binding site of CHIKV nsP3 macrodomain and nearby subsites. With the help of BioSolveIT, we want to progress these fragment hits into lead-like molecules with on-scale potency.
Jasmin Cara intends to achieve the following milestones:
- Design fragment merges and elaborations; enumerate designs; dock and score designs, then down-sample the compounds for purchase using HIPPO.
- Select the most promising compounds for purchase and validate using X-ray crystallography and GCI.
- Publish the obtained data in the Protein Data Bank and peer-reviewed journal.