Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

Hussain, Tariq; Zhao, Deming; Shah, Syed Zahid Ali; Sabir, Naveed; Wang, Jie; Liao, Yi; Song, Yinjuan; Dong, Haodi; Mangi, Mazhar Hussain; Ni, Jiamin; Yang, Lifeng; Zhou, Xiangmei

doi:10.3390/cells8050506

Cited by 38 publications

(25 citation statements)

References 65 publications

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“…Nilotinib, a second-generation small-molecule tyrosine kinase inhibitor, is widely used in the treatment of chronic myeloid leukemia. 18 Studies have shown that Nilotinib has a potential antiviral effect. 19 Our docking results showed that Nilotinib was mainly combined with the interface between NSP12 and NSP7 of SARS-CoV-2 through van der Waals potential energy and hydrogen bonds, involving LYS-411 ( Figure 2A).…”

Section: F I G U R Ementioning

confidence: 99%

SARS‐CoV‐2 and SARS‐CoV: Virtual screening of potential inhibitors targeting RNA‐dependent RNA polymerase activity (NSP12)

Ruan

Liu

Guo

et al. 2020

Journal of Medical Virology

115

107

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Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the harm caused by coronaviruses to the world cannot be underestimated. Recently, a novel coronavirus (severe acute respiratory syndrome coronavirus‐2 [SARS‐CoV‐2]) initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has infected more than six million people worldwide by 21 June 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 200 countries around the world. However, the effective drug has not yet been officially licensed or approved to treat SARS‐Cov‐2 and SARS‐Cov infection. NSP12‐NSP7‐NSP8 complex of SARS‐CoV‐2 or SARS‐CoV, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12‐NSP7‐NSP8 complex (PDB ID: 7BW4) structure of SARS‐CoV‐2 and the NSP12‐NSP7‐NSP8 complex (PDB ID: 6NUR) structure of SARS‐CoV, NSP12‐NSP7 interface model, and NSP12‐NSP8 interface model were established for virtual screening in the present study. Eight compounds (Nilotinib, Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All eight compounds can combine well with NSP12‐NSP7‐NSP8 in the crystal structure, providing drug candidates for the treatment and prevention of coronavirus disease 2019 and SARS.

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Section: F I G U R Ementioning

confidence: 99%

SARS‐CoV‐2 and SARS‐CoV: Virtual screening of potential inhibitors targeting RNA‐dependent RNA polymerase activity (NSP12)

Ruan

Liu

Guo

et al. 2020

Journal of Medical Virology

115

107

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“…51 Tyrosine kinase inhibitors that have been studied extensively in tumour models, such as nilotinib, are now showing promising pharmacological expansion of protective innate immunity to mycobacterial infections. 52 These compounds are attractive candidates for testing as a prophylactic anti-TB regimen in highrisk communities.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Therapeutic host-directed strategies to improve outcome in tuberculosis

2020

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Bacille Calmette-Guérin (BCG) is the only licenced tuberculosis (TB) vaccine, but has limited efficacy against pulmonary TB disease development and modest protection against extrapulmonary TB. Preventative antibiotic treatment for Mycobacterium tuberculosis (Mtb) infections in high-prevalence settings is unfeasible due to unclear treatment durability, drug toxicity, logistical constraints related to directly observed treatment strategy (DOTS) and the lengthy treatment protocols. Together, these factors promote nonadherence, contributing to relapse and establishment of drug-resistant Mtb strains. Although antibiotic treatment of drugsusceptible Mtb is generally effective, drug-resistant TB has a treatment efficacy below 50% and can, in a proportion, develop into progressive, untreatable disease. Other immune compromising co-infections and/or co-morbidities require more complex prevention/treatment approaches, posing huge financial burdens to national health services. Novel TB treatment strategies, such as host-directed therapeutics, are required to complement pathogen-targeted approaches. Pre-clinical studies have highlighted promising candidates that enhance endogenous pathways and/or limit destructive host responses. This review discusses promising pre-clinical candidates and forerunning compounds at advanced stages of clinical investigation in TB host-directed therapeutic (HDT) efficacy trials. Such approaches are rationalized to improve outcome in TB and shorten treatment strategies.

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“…TNF-α inhibitors and LT-α inhibitors, highly successful in cancer treatment, also show potential for repurposing, as an in vitro granuloma model reveals their ability to resuscitate dormant TB via controlled immunosuppression [ 64 ]. There is a recent burst of exploration into similar molecules, such as nilotinib, gefitinib and fostamatinib, each showing varied mechanisms of action, for example, enhancing autophagy [ 65 , 66 , 67 ].…”

Section: Repurposing Immunomodulatory Compoundsmentioning

confidence: 99%

The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review

Lee

Bhakta

2021

Antibiotics

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Tuberculosis (TB) remains a global health emergency, with an estimated 2 billion people infected across the world, and 1.4 million people dying to this disease every year. Many aspects of the causative agent, Mycobacterium tuberculosis, make this disease difficult for healthcare and laboratory researchers to fight against, such as unique pathophysiology, latent infection and long and complex treatment regimens, thus causing patient non-compliance with the treatment. Development of new drugs is critical for tackling these problems. Repurposing drugs is a promising strategy for generating an effective drug treatment whilst circumventing many of the challenges of conventional drug development. In this regard, the incorporation of immunomodulatory drugs into the standard regimen to potentiate frontline drugs is found to be highly appealing. Drugs of diverse chemical classes and drug categories are increasingly being evidenced to possess antitubercular activity, both in vitro and in vivo. This article explores and discusses the molecular entities that have shown promise in being repurposed for use in anti-TB adjunctive therapy and aims to provide the most up-to-date picture of their progress.

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Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy

Cited by 38 publications

References 65 publications

SARS‐CoV‐2 and SARS‐CoV: Virtual screening of potential inhibitors targeting RNA‐dependent RNA polymerase activity (NSP12)

SARS‐CoV‐2 and SARS‐CoV: Virtual screening of potential inhibitors targeting RNA‐dependent RNA polymerase activity (NSP12)

Therapeutic host-directed strategies to improve outcome in tuberculosis

The Prospect of Repurposing Immunomodulatory Drugs for Adjunctive Chemotherapy against Tuberculosis: A Critical Review

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