Ponatinib and other clinically approved inhibitors of Src and Rho-A kinasesabrogate dengue virus serotype 2- induced endothelial permeability
Year: 2024
Type: article
Abstract: Ponatinib and other clinically approved inhibitors of Src and Rho-A kinasesabrogate dengue virus serotype 2- induced endothelial permeability Srishti Rajkumar Mishra 1#, Ayan Modak1, Mansi Awasthi1#, Archana Sobha 2, Easwaran Sreekumar1,3* 1Molecular Virology Laboratory; 2Animal Research Facility, Rajiv Gandhi Centre forBiotechnology (RGCB), Thiruvananthapuram 695014, Kerala, India3Molecular Bioassay Laboratory, Institute of Advanced Virology (IAV), Bio360 LifeSciences Park, Thiruvananthapuram-695317, Kerala, India#Regional Centre for Biotechnology (RCB), Faridabad, New Delhi *Corresponding author (Easwaran Sreekumar; Molecular Virology Laboratory; RajivGandhi Centre for Biotechnology (RGCB), Thycaud P.O, Thiruvananthapuram695014, Kerala, India; Tel:+91-9447698943; E-mail: [email protected];) Severe dengue often presents as shock syndrome with enhanced vascular permeability and plasma leakage into tissue spaces. In vitro studies have documented the role of Src family kinases (SFKs) and RhoA-kinases (ROCK) in dengue virus serotype 2 (DENV2)-induced endothelial permeability. Here, we show that the FDA-approved SFK inhibitors Bosutinib, Vandatenib and Ponatinib, as well as the ROCK inhibitors, Netarsudil and Ripasudil significantly inhibit DENV2-induced endothelial permeability. In cultured telomerase immortalized human microvascular endothelial cells (HMEC-1), treatment with these inhibitors reduced the phosphorylation of VE-Cadherin, Src and myosin light chain 2 (MLC2) proteins that were upregulated during DENV2 infection. It also prevented the loss of VE-cadherin from the inter-endothelial cell junctions induced by viral infection. In in-vivo studies using DENV2-infected AG129 IFN receptor-a/b/g deficient mice, ponatinib, when administered 24h post-infection onwards, demonstrated significant benefits in improving body weight, clinical outcomes, and survival rates. While all virus-infected, untreated mice died by day-10 post-infection, 80% of the ponatinib-treated mice survived, and approximately 60% were still alive at the end of the 15-day observation period. The treatment also significantly reduced disease severity factors such as vascular leakage, thrombocytopenia; and restored liver function. Comparable effects were observed even when ponatinib treatment was initiated after symptom onset. The results highlight ponatinib as an effective therapeutic option in severe dengue; and also a similar potential for other FDA- approved SFK and ROCK inhibitors.
Source: Figshare
Author: Sreekumar, Eswaran
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6977128007
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