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Insights into interactomics-driven drug repurposing to combat COVID-19
Published in Sanjeeva Srivastava, Multi-Pronged Omics Technologies to Understand COVID-19, 2022
Amrita Mukherjee, Ayushi Verma, Ananya Burli, Krishi Mantri, Surbhi Bihani
Proteomics-based approaches (Figure 9.1) allow for an unbiased, data-driven target identification that would eventually raise the success rate of the drug repositioning program. Recently, scientists were able to identify Ivermectin, a broad-spectrum, FDA-approved antiparasitic drug, as a possible treatment option for COVID-19 using repurposing approach (Li, Zhao, and Zhan 2021). Using label-based quantitative proteomics, they studied the proteome signature in response to Ivermectin and identified many proteins dysregulated due to SARS-CoV-2 infection (Bojkova et al. 2020) to be involved in Ivermectin-regulated pathways. In another study, Ivermectin was shown to inhibit SARS-CoV-2 replication in vitro (Caly et al. 2020) and was found to be safe and effective for treating mild COVID-19 in a small group of patients in Bangladesh (Ahmed et al. 2021). The clinical trial results for ivermectin are currently awaited (ClinicalTrials.gov Identifier: NCT04668469).
Antimalarial and Other Antiparasitic Drugs
Published in Richard J. Sundberg, The Chemical Century, 2017
Merck scientists also examined the activity of ivermectin against Onchocerca volvulus, the parasitic worm that is the causal agent of river-blindness in Africa. In cooperation with the WHO, ivermectin was tested and approved for human use in 1987 under the name Mectizan. Because infected persons are normally impoverished, Merck donated the drug. Since 2002, the program has been administered by the African Programme for Onchoceriasis Control of the WHO. Ivermectin has very low toxicity and can be administered with little medical supervision. Ivermectin kills only immature filarial and must be administered periodically.21 It is used in combination with two other antiparasitic drugs albendazole and DEC.
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
In contrast to DAF-12, NHR-8 has emerged as one of the most important regulators of xenobiotic detoxification in C. elegans, as it controls gene activation in response to xenobiotic exposure and is required for organismal resistance to some compounds. Lindblom, Pierce, and Sluder (2001) first showed that nhr-8 mutation or RNAi rendered worms sensitive to the toxins colchicine and chloroquine. Menez et al. (2019) demonstrated that nhr-8 mutants displayed hypersensitivity to the anthelmintic ivermectin, with nhr-8 silencing in ivermectin-resistant worms enhancing drug efficacy. At the gene regulation level, nhr-8 mutant worms exhibited reduced expression of several phase I, II, and III detoxification genes, including pgp and cyp genes known to impact ivermectin tolerance in C. elegans, with correspondingly diminished ABC transporter-mediated drug efflux activity (Menez et al. 2019). Importantly, re-expression of the ABC transporter pgp-6 in nhr-8 mutant worms elevated tolerance to ivermectin, implicating NHR-8 control of ABC drug efflux transporters as a likely mechanism for drug resistance. Support for this model is provided by Guerrero et al. (https://www.biorxiv.org/content/10.1101/823302v1.full), who noted that induction of three pgp phase III detoxification genes by glycosylation inhibitor tunicamycin required nhr-8; that nhr-8 loss-mediated acute tunicamycin sensitivity while NHR-8 overexpression produced tunicamycin resistance; and that chemical inhibition of pgp glycoproteins suppressed tunicamycin resistance. Collectively, evidence suggests that NHR-8 is essential to induce many phase I, II, and III detoxification genes in worms exposed to various toxins, perhaps especially phase III drug efflux transporters. Notably, the role of NHR-8 is xenobiotic-specific, as Lindblom, Pierce, and Sluder (2001) found that loss of nhr-8 rendered worms sensitive to only some, but not all tested xenobiotics. Indeed, NHR-8 likely possesses redundant functions with other transcriptional regulators in regulating xenobiotic detoxification genes, as other studies showed that NHR-8 depletion alone did not broadly abrogate the expression of select phase I and II genes (Chamoli et al. 2014; Jones et al. 2013). Rather, Chamoli et al. (2014) reported that PHA-4/FoxA, NHR-8, and AHR-1 cooperatively induce various cyp and ugt genes, albeit in a long-lived mutant background, rather than in acute exposure to xenobiotic compounds.