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New Chemical Scaffolds to Selectively Target the Trypanothione Metabolism
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
In addition to antimonials, several metals, such as As(III), gold(I) and silver derivatives, are effective against Leishmania (Colotti et al. 2018). One of the target of these metals is the trypanothione reductase. Baiocco and coworkers have shown that As2O3 is able to inhibit TR of L. infantum in the micromolar range but with an inhibition constant one order of magnitude higher that antimonials (Ki = 14 ± 4 μM) (Baiocco et al. 2009a). The ability to bind the cysteines makes gold compounds able to inhibit TR with high efficiency. Auranofin (12, Table 3), used for decades against rheumatoid arthritis (Colotti et al. 2018), is also able to inhibit L. infantum TR. Indeed, auranofin is able to inactivate the enzyme with high efficiency (Ki = 0.15 ± 0.04 μM), thereby killing the parasite in the promastigote stage (IC50 = 9.7 ± 1.0 μM). The low-resolution crystal structure of auranofin–TR complex allowed the comprehension of the molecular basis of this inhibition (Ilari et al. 2012). As expected, the gold ion was found to be tightly bound to the two catalytic cysteines (Cys52 and Cys57) in the active site of the enzyme, thereby hampering hydride transfer from the protein to trypanothione, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin inhibits TR through a dual mechanism (Figure 4B and 4C).
A-Z of Standardisation, Pre-Clinical, Clinical and Toxicological Data
Published in Saroya Amritpal Singh, Regulatory and Pharmacological Basis of Ayurvedic Formulations, 2017
Analgesic: SwarnaBhasma and Kushta TilaKalan (25-50 mg/kg, p.o.) and Auranofin (2.5-5.0 mg/kg, p.o.) exhibited analgesic activity against chemical (acetic acid induced writhing), electrical (pododolorimeter), thermal (Eddy’s hot plate and analgesiometer) and mechanical (tail clip) test. While the analgesic effects of Swarna Bhasma and Kushta Tila Kalan could be partly blocked by pretreatment with naloxone (1-5 mg/ kg, i.p., -15 min), such antagonism was not discernible with Auranofin at the doses used (Bajaj and Vohora 1998).
Entamoeba histolytica
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Mineko Shibayama, Nidia León-Sicairos, Jesús Serrano-Luna, Mireya de la Garza
A comparative study of experimental cecal amoebiasis to evaluate amoebicides in the mouse, hamster, and rat was developed in India. The authors found different responses for each animal and proposed the mouse model as the most useful for the primary screening of antiamoebic compounds [97,98]. In another study, the cytotoxic effect of amide derivatives of trifluoromethionine (TFM) against E. histolytica was evaluated. Amoebae but not mammals possess l-methionine γ-lyase, an enzyme that hydrolyzes TFM and its derivatives, which makes it a good target for amoebicidal activity [99]. Interestingly, a high-throughput screening for compounds effective against amoeba identified auranofin, an FDA-approved drug used therapeutically against rheumatoid arthritis. Auranofin is 10 times more potent than Mtz, which makes it a promising therapy for amoebiasis [100]. The innate immune response by protein lactoferrin, an iron-chelating molecule that is responsible for avoiding pathogens to acquire iron in mucosae and infection sites, has been tested in ALA and IA [101,102]. Remarkably, bovine lactoferrin was able to cure ALA and synergize with Mtz in biological action. This observation is particularly important given that a reduced dose of Mtz can be used if combined with lactoferrin, with the same effect on the parasite, thus diminishing the side effects and toxicity of the drug. In addition, other properties of lactoferrin such as its anti-inflammatory activity can help resolve the amoebic abscesses [101].
The management of Babesia, amoeba and other zoonotic diseases provoked by protozoa
Published in Expert Opinion on Therapeutic Patents, 2023
Clemente Capasso, Claudiu T. Supuran
Although there are ongoing studies, there is currently neither a vaccine nor a wide range of medications that are effective against amebiasis, which remains one of the most severe enteropathogens worldwide [38]. Patients with the clinical disease can be treated with an amoebicidal tissue-active agent or a luminal cysticidal agent to stop the infection and avoid further infections [47,48]. The amoebicidal drug includes the nitroimidazole agents, such as metronidazole 13 and tinidazole 14 (Figure 3), which are the treatment of choice for amebic colitis and amebic liver disease due to their potency against the parasites’ reproductive stages (trophozoites) [47,48]. Tinidazole has a longer half-life and is better tolerated, although metronidazole kills the parasites more efficiently [47,48]. It is necessary to use a luminal agent after using nitroimidazole because it does not eradicate luminal cysts [49–51]. The aminoglycoside paromomycin 15 is utilized as a luminal cysticidal agent, which should not be provided concurrently with the nitroimidazole agent [52]. Alternatives include diloxanide furoate 16 and iodoquinol 17 (Figure 3) [38]. Recently, auranofin, a gold compound used to treat particular cases of rheumatoid arthritis, has entered early clinical drug development as an antiparasitic agent [53]. However, more research is needed to evaluate if auranofin would be a successful treatment of amebiasis and if its usage will be limited by known safety issues such as diarrhea, rash, and bone marrow suppression [53].
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
Due to the critical and unmet need for developing new anti-CDI therapeutics, researchers have turned their attention to re-purposing drugs with well-studied safety and pharmacokinetic profiles. Auranofin (6; Figure 2) is a gold-containing anti-inflammatory FDA-approved anti-rheumatoid arthritis drug which possesses strong antibacterial and antifungal activities [125]. Similar to the anticlostridial antibiotic fidaxomicin, auranofin was observed to inhibit C. difficile growth, toxin production, and spore formation. Auranofin also produced a direct protective effect against C. difficile toxin-mediated inflammation in an in vitro assay, which was not observed with fidaxomicin [125,126]. Upon testing in a mouse model of CDI, auranofin significantly protected mice against CDI at low clinically achievable doses (0.125 mg/kg and 0.25 mg/kg) with 100% and 80% survival, respectively Auranofin is a promising candidate, with an unknown mechanism of action, which warrants further investigation as a novel treatment option for CDI.
Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads
Published in Expert Review of Anti-infective Therapy, 2021
A subset of compounds available in a high-value Repurposing, Focused Rescue and Accelerated MEdicinal chemistry (ReFRAME) library also identified FDA-approved panobinostat displaying a nanomolar potency. In addition, FDA orphan drug lestaurtinib was also found highly potent against N. fowleri [38]. Another FDA-approved drug auranofin was identified as a priority anti-N. fowleri compound in this study (Table 1). Auranofin, a broad-spectrum anti-parasitic agent, was shown to be active against the US strains [39], as well as against the strains of various genotypes originated from different geographic regions [40]. Auranofin is a known inhibitor of selenoprotein synthesis [41] and thioredoxin reductase function [42–46], which is involved in protecting cells from damage caused by oxidative stress. Consistent with the targeting of redox enzymes, exposure to auranofin led to accumulation of reactive oxygen species in N. fowleri trophozoites [40].