Inhibition of Chikungunya virus by an adenosine analog targeting the SAM‐dependent nsP1 methyltransferase

Mudgal, Rajat; Mahajan, Supreeti; Tomar, Shailly

doi:10.1002/1873-3468.13642

Cited by 46 publications

(43 citation statements)

References 62 publications

(79 reference statements)

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“…can thus be targeted at each of these steps of their life cycle to combat infections caused by them (39). Antiviral drugs blocking entry of virus or acting on replication stages have been reported against dengue, chikungunya virus and other similar RNA viruses (40,41). Studies suggest that targeting the capsid synthesis step could also prevent budding stage of virus (42,43).…”

Section: Discussionmentioning

confidence: 99%

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

2020

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The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) associated Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific molecular interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising molecules for both the targets, which were further analyzed in details by their binding energy, binding modes through molecular docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified molecules may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified.

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Section: Discussionmentioning

confidence: 99%

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

2020

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“…Resistance selection unveiled two mutations G230R and K299E in nsP1 to develop resistance against both compounds [ 38 ]. Additionally, 5-iodotubercidin (5-IT, Figure 2 ) showed also an inhibitor of the MTase activity of nsP1 in a capillary electrophoresis-based assay [ 39 ]. This derivate of tubercidine and a known adenosine kinase inhibitor demonstrated potent anti-CHIKV activity in a plaque-reduction assay [ 39 ].…”

Section: Virus Targeting Inhibitorsmentioning

confidence: 99%

Antivirals against the Chikungunya Virus

Battisti

Urban

Langer

2021

Viruses

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

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“…5-Iodotubercidin, an adenosine analogue, was recently discovered by screening with a novel capillary electrophoresis-based assay for MTase activity of CHIKV nsP1. The activity of the compound in this enzymatic assay was validated in cell culture ( 66 ). This enzymatic assay uncouples the MTase and GTase activities and thus can be used to identify specific alphavirus nsP1 MTase inhibitors.…”

Section: Nonstructural Protein 1 (Nsp1)mentioning

confidence: 99%

Small-Molecule Inhibitors of Chikungunya Virus: Mechanisms of Action and Antiviral Drug Resistance

Kovacikova

Hemert

2020

Antimicrob Agents Chemother

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has spread to more than 60 countries worldwide. CHIKV infection leads to a febrile illness known as Chikungunya fever (CHIKF), which is characterized by long-lasting and debilitating joint and muscle pain. CHIKV can cause large-scale epidemics with high attack rates, which substantiates the need for development of effective therapeutics suitable for outbreak containment. In this review, we highlight the different strategies used for developing CHIKV small-molecule inhibitors, ranging from high-throughput cell-based screening, in silico screens and enzymatic assays with purified viral proteins. We further discuss the current status for the most- promising molecules including in vitro and in vivo findings. In particular, we focus on describing host and/or viral targets, mode of action and mechanisms of antiviral drug resistance and associated mutations. Knowledge of the key molecular determinants of drug resistance will aid selection of the most promising antiviral agent(s) for clinical use. For these reasons, we also summarize the available information about drug-resistant phenotypes in Aedes mosquito vectors. From this review, it is evident that more of the active molecules need to be evaluated in pre-clinical and clinical models to address the current lack of antiviral treatment for CHIKF.

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Inhibition of Chikungunya virus by an adenosine analog targeting the SAM‐dependent nsP1 methyltransferase

Cited by 46 publications

References 62 publications

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach

Antivirals against the Chikungunya Virus

Small-Molecule Inhibitors of Chikungunya Virus: Mechanisms of Action and Antiviral Drug Resistance

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