IISER MOHALI

Primarily platelet factor 4 (PF4 or CXCL4) promotes the blood coagulation at the site of injury to stop bleeding. PF4 is secreted from the activated platelets during several disease conditions including dengue virus (DENV) infection. Plasma level of PF4 increases more than 10 folds during 1-5 days of infection in DENV patients. PF4 is proviral for DENV propagation and it’s plasma level correlates with infection severity in patients and mice models. It decreases interferon (IFN) synthesis and response by the immune cells against DENV infection. We developed a small molecule, namely 7D, antagonist to CXCR3 (receptor for PF4), which promotes synthesis of IFNs by blocking PF4 interaction with CXCR3, and inhibits DENV2 infection in mice. It is effective against all 4 serotypes of DENV in vitro. Having the inhibitory effect on SIRT-1, the 7D also promotes B cell proliferation and Ig synthesis, finally increases DENV-neutralizing Ig level in mice. Currently we are testing its effects in non-human primate (NHP) model of DENV infection. Besides, we are developing combination therapy of 7D with G4KKO (PF4 neutralizing IgG) against DENV2 infection in mice models. Also, developing combination therapy of 7D with A2iP (blocks gut or blood vessel leakage) to rescue vascular leakage in DENV infection in mice models. Ultimate goal to develop successful therapeutic regimen against dengue.