Evolution of efficacious pangenotypic hepatitis C virus therapies

Ashraf, Muhammad Usman; Iman, Kanzal; Khalid, Muhammad Farhan; Salman, Hafiz Muhammad; Shafi, Talha; Rafi, Momal; Javaid, Nida; Hussain, Rashid; Ahmad, Fayyaz; Shahzad‐ul‐Hussan, Syed; Mirza, Shaper; Shafiq, Muhammad; Afzal, Samia; Hamera, Sadia; Anwar, Saeed; Qazi, Romena; Idrees, Muhammad; Qureshi, Saima; Chaudhary, Safee Ullah

doi:10.1002/med.21554

Cited by 15 publications

(10 citation statements)

References 328 publications

(352 reference statements)

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“…Over the last decade, computer aided drug discovery has emerged as a fundamental tool in drug discovery and design process [45][46][47][48]. Identification of compounds that bind and inhibit normal function of proteins involved in viral replication has been the most successful strategy in direct acting antiviral drug discovery [49][50][51][52]. In this study, we used a virtual screening based strategy to identify already approved drugs or drug-like molecules that can bind to any of the three key viral enzymes, 3CL-protease, RdRp and helicase, and potentially inhibit the function of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Iftikhar

Ali

Farooq

et al. 2020

Computers in Biology and Medicine

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The recent outbreak of coronavirus disease-19 (COVID-19) continues to drastically affect healthcare throughout the world. To date, no approved treatment regimen or vaccine is available to effectively attenuate or prevent the infection. Therefore, collective and multidisciplinary efforts are needed to identify new therapeutics or to explore effectiveness of existing drugs and drug-like small molecules against SARS-CoV-2 for lead identification and repurposing prospects. This study addresses the identification of small molecules that specifically bind to any of the three essential proteins (RdRp, 3CL-protease and helicase) of SARS-CoV-2. By applying computational approaches we screened a library of 4574 compounds also containing FDA-approved drugs against these viral proteins. Shortlisted hits from initial screening were subjected to iterative docking with the respective proteins. Ranking score on the basis of binding energy, clustering score, shape complementarity and functional significance of the binding pocket was applied to identify the binding compounds. Finally, to minimize chances of false positives, we performed docking of the identified molecules with 100 irrelevant proteins of diverse classes thereby ruling out the non-specific binding. Three FDA-approved drugs showed binding to 3CL-protease either at the catalytic pocket or at an allosteric site related to functionally important dimer formation. A drug-like molecule showed binding to RdRp in its catalytic pocket blocking the key catalytic residues. Two other druglike molecules showed specific interactions with helicase at a key domain involved in catalysis. This study provides lead drugs or drug-like molecules for further in vitro and clinical investigation for drug repurposing and new drug development prospects.

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Section: Discussionmentioning

confidence: 99%

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Iftikhar

Ali

Farooq

et al. 2020

Computers in Biology and Medicine

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show abstract

“…The full genetic information of HCV is localized in its positive-stranded RNA; unlike the HBV, the HCV genome does not need to enter the nucleus and integrate into the chromosome of infected hepatocytes 76 . Hence, HCV-RNA can be directly translated in the hepatocyte cytoplasm after endocytosis and uncoating, which are mediated by pH-dependent fusion with the lysosome 77 .…”

Section: Hcv-induced Hepatoma Cells' Transformationmentioning

confidence: 99%

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

et al. 2020

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Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

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“…An effective immune response clears about 20% of HCV infections. However, without an adequate immune response, the virus will continue to replicate and cause a chronic infiltration of inflammatory cells into the liver [51]. Similar to hepatitis B, IL22-producing Th17 cells also increased significantly in the liver of patients with chronic hepatitis C [52].…”

Section: Hepatitis Cmentioning

confidence: 99%

Interleukin 22 in Liver Injury, Inflammation and Cancer

Wu¹,

Min²,

Ge³

et al. 2020

Int. J. Biol. Sci.

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Interleukin 22(IL-22), a member of the IL-10 cytokine family and is an emerging CD4+Th cytokine that plays an important role in anti-microbial defense, homeostasis and tissue repair. We are interested in IL-22 as it has the double function of suppressing or encouraging inflammation in various disease models including hepatic inflammation. As a survival factor for hepatocytes, IL-22 plays a protective role in many kinds of liver diseases, such as hepatitis, liver fibrosis, or hepatocellular carcinoma (HCC) by binding to the receptors IL-22R1 and IL-10R2. Overexpression of IL-22 reduces liver fibrosis by attenuating the activation of hepatic stellate cell (the main cell types involved in hepatic fibrosis), and down-regulating the levels of inflammatory cytokines. Administration of exogenous IL-22 increases the replication of hepatocytes by inhibiting cell apoptosis and promoting mitosis, ultimately plays a contributing role in liver regeneration. Furthermore, treatment with IL-22 activates hepatic signal transducer and activator of transcription 3 (STAT3), ameliorates hepatic oxidative stress and alcoholic fatty liver, effectively alleviate the liver damage caused by alcohol and toxicant. In conclusion, the hepatoprotective functions and liver regeneration promoting effect of IL-22 suggests the therapeutic potential of IL-22 in the treatment of human hepatic diseases.

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Evolution of efficacious pangenotypic hepatitis C virus therapies

Cited by 15 publications

References 328 publications

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

Interleukin 22 in Liver Injury, Inflammation and Cancer

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