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Antifungals
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
A. S. Ibrahim, R. Prasad, M. A. Ghannoum
Cerulenin is an antifungal isolated from the culture filtrate of Cephalosporium caerulens. It strongly inhibits the growth of yeast-type fungi such as Saccharomyces, Candida and Cryptococcus, and moderately inhibits the growth of filamentous fungi and Gram-positive and -negative bacteria in vitro.64 Cerulenin is a potentially useful and convenient modulator of lipid composition in microorganisms. A number of investigators have studied its mechanism of action.64-68
Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy
Published in Expert Opinion on Investigational Drugs, 2018
Alejandro Schcolnik-Cabrera, Alma Chávez-Blanco, Guadalupe Domínguez-Gómez, Lucia Taja-Chayeb, Rocio Morales-Barcenas, Catalina Trejo-Becerril, Enrique Perez-Cardenas, Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Up to date, the first FASN inhibitor has entered into clinical trials [72]. Early in 1972, the antifungal cerulenin was the first FASN inhibitor identified [73] and it was widely evaluated as an anticancer agent in experimental models, showing activity against a variety of tumor cell lines and xenograft models [74]. To avoid the highly reactive nature of the cysteine-reactive epoxide in cerulein, Kuhahda et al. in 2000 reported the synthesis and antitumor activity of the synthetic, chemically stable inhibitor of FASN, C75, which was proven to inhibit purified mammalian FASN as a slow-binding inhibitor and also by blocking fatty acid synthesis in human cancer cells [27]. Orlistat, a reduced form of the natural product lipstatin, was proposed as an antiobesity treatment in 1987 by virtue of its potency and selectivity to inhibit pancreatic lipase [75], but it was not until 1994 that Kridel et al. uncovered that orlistat was an irreversible inhibitor of FASN via the thioesterase (TE) domain of the enzyme. Moreover, orlistat showed potent antitumor effects in vitro and in vivo in the prostate cancer cell line PC-3 [76]. A number of other compounds have been—mainly natural—compounds have been demonstrated to inhibit by diverse mechanism the enzyme FASN, mostly at micromolar concentrations. Among these are epigallocatechin-3-gallate (EGCG), luteolin, quercetin, resveratrol, triclosan, curcumin, alpha-mangostatin, platensimycin, and tannic acid [72]. None of these is being in clinical development.
Toward the identification of ZDHHC enzymes required for palmitoylation of viral protein as potential drug targets
Published in Expert Opinion on Drug Discovery, 2020
Mohamed Rasheed Gadalla, Michael Veit
Although ZDHHC genes have been linked to a variety of human diseases, especially cancer and neurological disorders [17,22,183,184], no drug specific for a certain ZDHHC-substrate interaction has been developed so far. One widely used in research is 2-bromo-palmitate, which forms by its second carbon an irreversible covalent bond with the thiolate group of the catalytic cysteine in the DHHC motif (Figure 2). However, 2-BP as well as other ‘palmitoylation inhibitors’, such as cerulenin and triascin inhibits other enzymes of lipid metabolism [24].
Emerging therapeutic targets for retinoblastoma
Published in Expert Opinion on Therapeutic Targets, 2022
Radhika Manukonda, Revu VL Narayana, Swathi Kaliki, Dilip K Mishra, Geeta K Vemuganti
Menendez and Alarcon introduced the term ‘metabostemness’ for explaining the role of cellular metabolic changes responsible for genetic and epigenetic adaptations, required for reprogramming normal/tumor cells into CSCs [95]. Apart from two crucial epigenetic modifications namely DNA methylation and histone modification, the epigenetic regulation of cell differentiation genes is also crucial for exerting metabolic effects on nuclear reprogramming. These metabolic transformations occur before the changes in stemness happen. The accumulation of by-products of normal metabolism or onco-metabolites causes aberrant signal transduction resulting in initiation and progression of carcinogenesis eventually blocking the acquisition of differentiation markers thereby inducing the expression of stemness genes likely through epigenetic mechanisms [96]. Targeting these metabolic processes specific to CSCs is considered to be one of the new approaches to specifically eliminate this subgroup from the bulk of the tumor. Likewise, novel therapeutic strategies to target common metabolic pathways for all tumor cells such as glycolysis and lipid metabolism are emerging. Vandhana et al. showed that inhibitors of fatty acid synthase (FASN) such as cerulenin, triclosan, and orlistat induced DNA damage, apoptosis along with enhanced lipid peroxidation in Y79 Rb cells. Altered lipid distribution was observed in tumor cells compared to normal cells, suggesting the involvement of metabolites in Rb tumor biology, and they could serve as therapeutic targets [97]. In a recent study, Sahoo et al. used a constraint-based metabolic modeling approach for understanding the Rb-specific usage of biochemical pathways for survival. The results revealed that tumor cells utilized arginine, gamma-aminobutyric acid (GABA), glutamate, and ornithine metabolism for deriving cellular energy. Further, analysis of novel metabolic secretion profiles identified novel lipid and nucleoside transport proteins that could serve as therapeutic targets for Rb [98].