Dash Rudra Narayan, Ray Amrita, Mamidi Prabhudutta, De Saikat, Mohapatra Tapas K, Moharana Alok K, Mukherjee Tathagata, Ghosh Soumyajit, Chattopadhyay Subhasis, Subudhi Bharat B, Chattopadhyay Soma
Drug Development and Analysis Lab, School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to be University, Kalinga Nagar, Bhubaneswar 751003, Odisha, India.
Infectious Disease Biology, Institute of Life Sciences, NALCO square, Bhubaneswar 751023,Odisha, India.
ACS Omega. 2023 Dec 21;9(1):146-156. doi: 10.1021/acsomega.3c00763. eCollection 2024 Jan 9.
There is no approved antiviral for the management of the Chikungunya virus (CHIKV). To develop an antiviral drug that can manage both CHIKV and arthritis induced by it, an ester conjugate of telmisartan (TM) and salicylic acid (SA) was synthesized (DDABT1). It showed higher potency (IC of 14.53 μM) and a good selectivity index [(SI = CC/IC) > 33]. On post-treatment of DDABT1, CHIKV infection was inhibited significantly by reducing CPE, viral titer, viral RNA, and viral proteins. Further, the time of addition experiment revealed >95% inhibition up to 4hpi indicating its interference predominantly in the early stages of infection. However, the late stages were also affected. This conjugate of SA and TM was found to increase the antiviral efficacy, and this might be partly attributed to modulating angiotensin II (Ang II) receptor type 1 (AT1). However, DDABT1 might have other modes of action that need further investigation. In addition, the in vivo experiments showed an LD of 5000 mg/kg in rats and was found to be more effective than TM, SA, or their combination against acute, subacute, and chronic inflammation/arthritis . In conclusion, DDABT1 showed remarkable anti-CHIKV properties and the ability to reduce inflammation and arthritis, making it a very good potential drug candidate that needs further experimental validation.
目前尚无获批用于治疗基孔肯雅病毒（CHIKV）的抗病毒药物。为开发一种能够同时治疗CHIKV及其所致关节炎的抗病毒药物，合成了替米沙坦（TM）与水杨酸（SA）的酯共轭物（DDABT1）。它显示出更高的效力（IC为14.53 μM）和良好的选择性指数[（SI = CC/IC）> 33]。在DDABT1进行后处理时，通过降低细胞病变效应、病毒滴度、病毒RNA和病毒蛋白，CHIKV感染受到显著抑制。此外，添加时间实验表明，在感染后4小时内抑制率> 95%，表明其主要在感染早期发挥干扰作用。然而，后期也受到了影响。发现SA和TM的这种共轭物可提高抗病毒功效，这可能部分归因于对1型血管紧张素II（Ang II）受体（AT1）的调节。然而，DDABT1可能还有其他作用方式需要进一步研究。此外，体内实验显示在大鼠中的半数致死量为5000 mg/kg，并且发现其在对抗急性、亚急性和慢性炎症/关节炎方面比TM、SA或它们的组合更有效。总之，DDABT1显示出显著的抗CHIKV特性以及减轻炎症和关节炎的能力，使其成为一种非常有潜力的药物候选物，需要进一步的实验验证。
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