Abstract
IntroductionThe emergence of drug resistance and cross-resistance to existing drugs has warranted the development of new antivirals for Herpes simplex viruses (HSV). Hence, we have designed this study to evaluate the anti-viral activity of 1-[(2-methyl benzimidazole-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (MBZM-N-IBT), against HSV-1.MethodMolecular docking was performed to assess the affinity of MBZM-N-IBT for HSV-1 targets. This was validated by plaque assay, estimation of RNA and protein levels as well as time of addition experiments in vitro.ResultMolecular docking analysis suggested the inhibitory capacity of MBZM-N-IBT against HSV-1. This was supported by the abrogation of the HSV-1 infectious viral particle formation with the IC50 value of 3.619 µM. Viral mRNA levels were also reduced by 72% and 84% for UL9 and gC respectively. MBZM-N-IBT also reduced the protein synthesis for gC and ICP8 significantly. While mRNA of ICP8 was not significantly affected, its protein synthesis was reduced by 47%. The time of addition experiment revealed the capacity of MBZM-N-IBT to inhibit HSV-1 at early as well as late stages of infection in the Vero cells. Similar effect of MBZM-N-IBT was also noticed in the Raw 264.7 and BHK 21 cells after HSV-1 infection. Supported by the in silico data, this can be attributed to possible interference with multiple HSV targets including the ICP8, ICP27, UL42, UL25, UL15 and gB proteins.ConclusionThese results along with the lack of acute oral toxicity and significant anti-inflammatory effects suggest its suitability for further evaluation as a non-nucleoside inhibitor of HSV.
Highlights
The emergence of drug resistance and cross-resistance to existing drugs has warranted the development of new antivirals for Herpes simplex viruses (HSV)
Supported by the in silico data, this can be attributed to possible interference with multiple HSV targets including the ICP8, ICP27, UL42, UL25, UL15 and gB proteins. These results along with the lack of acute oral toxicity and significant anti-inflammatory effects suggest its suitability for further evaluation as a non-nucleoside inhibitor of HSV
The affinity of MBZM‐N‐IBT for multiple drug targets of HSV‐1 The crystal structure of HSV thymidine kinase (PDB ID: 1KI3) co-crystallized with penciclovir was used in molecular docking as a control
Summary
The emergence of drug resistance and cross-resistance to existing drugs has warranted the development of new antivirals for Herpes simplex viruses (HSV). Herpes simplex viruses (HSV) are double-stranded DNA virus of Herpesviridae family. Infections due to Herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are very common in the world, where about 67% of the population is suffering from it (http://www.who.int/mediacentre/factsheets/fs400/en/). Infections due to Herpes Simplex Virus (HSV) are primarily managed by treatment with nucleoside derivatives including acyclovir, ganciclovir, penciclovir, valaciclovir, and famciclovir [4]. The emergence of drug resistance has posed a serious challenge to their efficacy. The mechanism of resistance is generally attributed to either mutation in HSV thymidine kinase (TK) or DNA polymerase [5].
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