Evaluation of novobiocin and telmisartan for anti-CHIKV activity

Tripathi, Praveen Kumar; Soni, Anjali; Yadav, Shiv Pratap Singh; Kumar, Ankit; Gaurav, Nitika; Raghavendhar, Siva; Sharma, Pradeep; Sunil, Sujatha; Ashish, .; Jayaram, B.; Patel, Ashok Kumar

doi:10.1016/j.virol.2020.05.010

Cited by 26 publications

(21 citation statements)

References 48 publications

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“…However, HST and HSD were consistently more effective in inhibiting the same protease with IC 50 values of 2.5 ± 0.4 (HST) and 7.1 ± 1.1 (HSD), thereby demonstrating the efficiency like other flavonoid molecules to inhibit the enzyme activity. On the other hand, our IC 50 values are in a comparable range to Novobiocin and Telmisartan with 2 and 5 µM, respectively (Table 1) [64].…”

Section: Plos Onesupporting

confidence: 54%

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

et al. 2021

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The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3pro of ZIKV and nsP2pro of CHIKV and, Hesperidin (HSD) against nsP2pro of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low µM range for HST against ZIKV NS2B/NS3pro (12.6 ± 1.3 µM) and against CHIKV nsP2pro (2.5 ± 0.4 µM). The IC50 for HSD against CHIKV nsP2pro was 7.1 ± 1.1 µM. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases.

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Section: Plos Onesupporting

confidence: 54%

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

et al. 2021

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“…2E ). Further, the IC 50 values were 31.96 and 7.02 μM for MBZM-N-IBT and telmisartan, respectively, from the graphs plotted (log concentration versus normalized response-variable slope) in GraphPad Prism software where telmisartan was used as positive control ( 24 ) ( Fig. 2F ).…”

Section: Resultsmentioning

confidence: 99%

MBZM-N-IBT, a Novel Small Molecule, Restricts Chikungunya Virus Infection by Targeting nsP2 Protease Activity In Vitro , In Vivo , and Ex Vivo

Ghosh

Keshry

et al. 2022

Antimicrob Agents Chemother

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“…Recently, Tripathi et al have corroborated this by demonstrating direct inhibition of the CHIKV-nsP2 protease activity as well as CHIKV infection in vitro (25). Thus, TM can be a potential drug for repurposing against CHIKV infection.…”

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confidence: 83%

Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/ PPAR-γ/MAPKs pathways

Mamidi

Ghosh

et al. 2021

Preprint

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Chikungunya virus (CHIKV) has re-emerged as a global public health threat. The inflammatory pathways of RAS and PPAR-γ are usually involved in viral infections. Thus, Telmisartan (TM) with known capacity to block AT1 receptor and activate PPAR-γ, was investigated against CHIKV. The anti-CHIKV effect of TM was investigated in vitro (Vero, RAW 264.7 cells and hPBMCs) and in vivo (C57BL/6 mice). TM was found to abrogate CHIKV infection efficiently (IC50 of 15.34-20.89µM in the Vero and RAW 264.7 cells respectively). Viral RNA and proteins were reduced remarkably with the TM driven modulation of host m-TOR signaling. Additionally, TM interfered in the early and late stages of CHIKV life cycle with efficacy in both pre and post-treatment assay. Moreover, the agonist of AT1 receptor and antagonist of PPAR-γ increased CHIKV infection suggesting TM’s anti-viral potential by modulating host factors. Besides, reduced activation of all major MAPKs, NF-κB (p65) and cytokines by TM through the inflammatory axis supported the fact that the anti-CHIKV efficacy of TM is partly mediated through the AT1/PPAR-γ/MAPKs pathways. Interestingly, at the human equivalent dose, TM abrogated CHIKV infection and inflammation significantly leading to reduced clinical score and complete survival of C57BL/6 mice. Additionally, TM reduced infection in hPBMC derived monocyte-macrophage populations in vitro. Hence, TM was found to reduce CHIKV infection by targeting both viral and host factors. Considering its safety and in vivo efficacy, it can be a suitable candidate in future for repurposing against CHIKV.

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Evaluation of novobiocin and telmisartan for anti-CHIKV activity

Cited by 26 publications

References 48 publications

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases

MBZM-N-IBT, a Novel Small Molecule, Restricts Chikungunya Virus Infection by Targeting nsP2 Protease Activity In Vitro , In Vivo , and Ex Vivo

Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/ PPAR-γ/MAPKs pathways

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