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Cryptosporidium
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Una Ryan, Nawal Hijjawi, Lihua Xiao
Progress in developing new anticryptosporidial drugs has been hampered due to limitations of in vitro culture systems for Cryptosporidium, an inability to genetically manipulate the organism, and the unique metabolic features in this parasite, which has a highly streamlined metabolism rendering many classic drug targets unavailable.5,147–149 However, the recent development of a continuous culture system for C. parvum89 and the application of CRISPR/Cas9 technology to genetically engineer the parasite150 have opened up new possibilities for the development of anticryptosporidial drugs. Essential core metabolic pathways, including energy metabolism, lipid synthesis, and purine salvage, present in Cryptosporidium, are currently being targeted, including fatty acyl-coenzyme A synthetases (LC-ACS)149 and the inosine 5′- monophosphate dehydrogenase (IMPDH) gene.5,151
Mechanisms of Hepatitis C Virus Clearance by Interferon and Ribavirin Combination
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Srikanta Dash, Partha K. Chandra, Kurt Ramazan, Robert F. Garry, Luis A. Balart
Both IFN-α and RBV inhibit HCV IRES–mediated translation through prevention of polyribosome formation. Western blot analysis shows that IFN-α and RBV each induce PKR and eIF2α levels (Figure 4.7a). RBV also blocks polyribosome loading of HCV IRES-GFP mRNA through the inhibition of cellular inosine-5’-monophosphate dehydrogenase (IMPDH) activity and induction of PKR and eIF2α phosphorylation. Knockdown of PKR or IMPDH prevented RBV induces HCV IRES–mediated GFP translation (Figure 4.7a–d). IFN-α treatment induces levels of PKR and eIF2α phosphorylation that prevent ribosome loading of HCV IRES-GFP mRNA in Huh-7 cells. Silencing of PKR expression in Huh-7 cells prevents the inhibitory effect of IFN-α on HCV IRES-GFP expression (Figure 4.7e–f). The combination of IFN-α and RBV treatment synergistically inhibits HCV IRES translation by using two different mechanisms involving PKR activation and depletion of intracellular guanosine pool through inhibition of IMPDH.
Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Juliusz Maksymilian Walczak, Dorota Iwaszkiewicz-Grześ, Michalina Ziomkowska, Magdalena Śliwka-Kaszyńska, Mateusz Daśko, Piotr Trzonkowski, Grzegorz Cholewiński
Inosine-5′-monophosphate dehydrogenase (IMPDH) is an enzyme responsible for oxidation of inosine-5′-monophosphate into xanthine-5′-monophosphate (XMP) exploiting water molecule as well as NAD+ redox potential. This biotransformation is crucial for proper cell growth due to the fact that it triggers guanyl nucleotides formation which serve as RNA and DNA precursors, the energy reservoir for translation process, the cofactor for G-proteins as well as glycosylation precursor. Depletion of guanine-based nucleotides, which is induced by redirecting biosynthesis into adenine-based nucleotides pathway, results in impairment of de novo and salvage route of purine and pyrimidine nucleotides biosynthesis. This misregulation proceeds from phosphoribosyl pyrophosphate synthetase (PRPP) and ribonucleotides reductase (RNR) stimulation dependence accruing from guanine and adenine nucleotides. When the previous one activates enzymes’ bioactivities, the latter one inhibits them. Eventually, enhancement of adenosine nucleotides pool effects in malfunctioning of rapidly proliferating human cells1.
The association of mycophenolate mofetil and human herpes virus infection
Published in Journal of Dermatological Treatment, 2020
Jenny Sung Won Yun, Tami Yap, Raymond Martyres, Johannes S. Kern, George Varigos, Laura Scardamaglia
Being a potent noncompetitive and reversible inhibitor of inosine-5′-monophosphate dehydrogenase (4,42), MMF inhibits the synthesis of guanine nucleotides and selectively prevents proliferation and activation of T and B-lymphocytes (43). The lymphocyte specificity makes MMF a favorable therapeutic option for its consequent reduced hepatorenal toxicity. MMF has been effectively used in solid organ transplantation since US Food and drug administration approval (3) and is now widely used as steroid-sparing therapy for many different autoimmune conditions. Its efficacy to treat lymphocyte mediated skin disease (44) gained its popularity in Dermatology, used as therapy for: dermatitis, autoimmune blistering diseases, psoriasis, connective tissue disorders, graft-versus-host disease and others including Cutaneous Crohn disease, erythema multiforme, erythema nodosum, leprosy, lichen planus, idiopathic nodular panniculitis, and sarcoidosis (39,40,45).
A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1)
Published in Xenobiotica, 2022
Lu Zhang, Bill Poland, Michelle Green, Shekman Wong, J. Greg Slatter
Approaches that model EHR of both the parent drug and the glucuronide are less common and are exemplified by ezetimibe and its phenolic glucuronide (Soulele and Karalis 2019) and the ester prodrug, mycophenolate mofetil and its acyl and phenolic glucuronides (Sam et al. 2009, Yau et al. 2009). EHR population PK and PK/PD of the active metabolite, mycophenolic acid (MPA) and its acyl glucuronide were described by a one-compartment model with first-order elimination in patients undergoing haematopoietic stem cell transplantation. The model was combined with a maximal inhibitory PD model to establish the relationship between MPA plasma concentrations and inosine-5′-monophosphate dehydrogenase activity (IMPDH) (Yoshimura et al. 2018).