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Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
In 2006, the yeast was genetically modified in order to produce more farnesyl pyrophosphate through the mevalonate pathway and to reduce its use for sterol biosynthesis (down regulation of squalene synthase). Moreover, the gene coding for amorphadiene synthase and CYP71AV1 from A. annua were introduced and a final concentration of 100 mg l–1 of artemisinic acid were produced (Ro et al., 2006).
Chemical Hybridization Approaches Applied to Natural and Synthetic Compounds for the Discovery of Drugs Active Against Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Elena Petricci, Paolo Governa, Fabrizio Manetti
Other diphenyl ethers, which bear a biphosphonic moiety at the terminal edge, are important compounds for antiparasitic treatments. Many parasites, including T. cruzi, have the ability to import cholesterol from the host. T. cruzi is, however, obligated to synthesize endogenous sterols, such as ergosterol and other 24-alkyl sterols, through the mevalonate pathway that progresses via the squalene synthase enzyme. Since both biphosphonate compounds and the 4-phenoxyphenoxyethyl thiocyanate WC-9 (38, Figure 9) are reported as inhibitors of squalene synthase of T. cruzi, their hybrid compounds (39–42) (Chao et al. 2016) were designed as putative antitrypanosomal agents with improved activity in comparison to the parent compounds. Unfortunately, they showed a weak activity toward T. cruzi amastigotes (EC50 values higher than 10 μM), although they are highly active toward T. gondii tachyzoite proliferation (EC50 values ranging from 0.67 to >10 μM). Diphenyl ether-biphosphonate hybrids as inhibitors of T. cruzi amastigotes.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The predominant transcription initiation sites of the CYP51A1 gene are in the liver, lung, kidney, and placenta 250 and 249 bp upstream from the translation site. A second site is at –100 bp with the absence of TATA and CAAT regions and is a GC-rich region in the promoter sequence (Guengerich 2005; Rozman et al. 1996). A sterol/sterol-regulatory element binding protein-dependent pathway regulates the expression of CYP51A1 in liver and other tissues. cAMP/cAMP-responsive element modulator regulates the expression of CYP51A1 in testis (Halder et al. 2002). LXRα regulates cholesterol biosynthesis by directly silencing the expression of CYP51A1 and squalene synthase (Wang et al. 2008).
Drugs and nanoformulations for the management of Leishmania infection: a patent and literature review (2015-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Mariana Verdan, Igor Taveira, Flávia Lima, Fernanda Abreu, Dirlei Nico
In Leishmania, the cytoplasmic membrane has ergosterol as a constituent, while the cytoplasmic membrane of mammals has cholesterol as the principal constituent [73]. The enzyme squalene synthase participates in the biosynthesis of ergosterol, therefore being a target enzyme that deserves attention. Wadanambi and colleagues recently demonstrated the inhibitory activity of seven phytochemicals that bind to the active site of the squalene synthase of Leishmania donovani and, consequently, promote enzymatic inhibition. Ergosterol biosynthesis is already a target used by amphotericin B, which corroborates the use of this pathway as a potential therapeutic target [74]. Another peculiar metabolic target in Leishmania is the thiol redox, in which the trypanothione reductase system participates in the parasite’s redox homeostasis. The increase in reactive oxygen species consequently breaks this redox homeostasis causing cellular damage [75].
Pharmacological effects of Artocarpus lakoocha methanol extract on inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway
Published in Pharmaceutical Biology, 2022
Tasleem Akhtar, Hafiz Muhammad Ishaq, Muhammad Shahzad
Squalene synthase enzyme catalyses the first committed step in the de novo cholesterol biosynthesis. Squalene synthase inhibitors reduce LDL cholesterol in circulation by upregulating the expression of hepatic LDL receptors in a way similar to statins (Tavridou et al. 2008). HMG Co-A reductase, a transmembrane protein, is of primary importance in the biosynthesis of lipids and is documented as the enzyme involved in the rate-limiting step in cholesterol biosynthesis, indicating the chief target for the cholesterol-lowering agents, i.e., statins (Istvan and Deisenhofer 2001; Kim et al. 2016). Simvastatin is the competitive inhibitor of HMG-CoA reductase (Xu et al., 2014). Our results showed the downregulation of mRNA expression levels of HMG-CoA reductase when treated with methanol leaves extract of A. lakoocha. These findings are in parallel to a previous study in which mRNA expression of HMG-CoA reductase was decreased when treated with a combination of four herbs (HVC1) and simvastatin (Kim et al. 2016).
Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Nidhi Gupta, Nikita Sharma, Sandeep K. Mathur, Ramesh Chandra, Surendra Nimesh
As discussed in the aforementioned sections, cardiovascular diseases, including hypercholesterolemia are treated with various combinational approaches that lower the level of LDL-C in the plasma by multiple mechanisms. Although these therapies are effective against the disease as discussed previously, certain side effects have been associated with them. For example, some adverse effects associated with statins therapy include muscular myopathy, cholestasis, rhabdomylosis, myoglobinuria, nausea, abdominal pain, chronic rticarial and alopecia [34]. In one of the meta-analysis studies, it was demonstrated that the use of statins was associated with increased risk of acute pancreatitis. The patients under study had no previous history of gallstone or alcohol related diseases. The incidence rate was found to increase in the first year of drug administration than the former ones [35]. Lapaquistat acetate, a squalene synthase inhibitor was terminated under advanced phases 2 and 3 of clinical trials. The study revealed that SSI could effectively lower the cholesterol level in a dose dependent manner. But, it was observed that it increased the alanine aminotransferase value with rare increase in bilirubin levels, thereby resulting in serious hepatic toxicity [28]. Studies suggest that the accumulation of metabolic substrate during the biosynthesis of cholesterol, leads to severe toxicity in liver [36]. In addition, all of these treatments have limited efficacy, tolerability, poor bioavailability and low-systemic circulation. As most of these drugs are administered orally, the circulation time of the drug is reduced because of the first-pass mechanism in liver and easily gets cleared by the gastrointestinal tract [37]. Therefore, an extensive pharmaceutical research is needed for the development of novel strategy, which improves the therapeutic index of the respective drug and maintains a balance between efficacy and toxicity.