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Encephalitozoon
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Alexandra Valencakova, Lenka Luptakova, Monika Halanova, Olga Danisova
During a microsporidial keratoconjuctivitis and ocular microsporidiosis, a local therapeutic agent called fumagillin is recommended and applied.80 Fumagillin is an antiangiogenetic factor containing an antibiotic derived from Aspergillus fumigatus. Fumagillin and its semisynthetic analogue TNP-470 exert their effect by binding to the metalloprotease methionine aminopeptidase type 2 (MetAP2) of the pathogen and inhibiting its activity. Clinical manifestations are alleviated in less than 1 week, but for the complete elimination of the pathogen, or to prevent the recurrence of infection, a long-term application of the drug is necessary.
Fumagillin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
The mechanism of action of fumagillin is thought to relate to inhibition of RNA synthesis and/or alteration of the DNA content of the organism (Diesenhouse et al., 1993; Chan et al., 2003), thereby resulting in interference with the meront and sporont stages of parasitic proliferation. Fumagillin and its derivatives bind and inhibit methionine amino peptidase {ğ} type 2 (MetAP2) (Upadhya et al., 2006).
Obesity medications in development
Published in Expert Opinion on Investigational Drugs, 2020
Candida J. Rebello, Frank L. Greenway
The MetAP2 inhibitor beloranib (ZGN-440, Zafgen), consistently produced clinically significant weight loss in patients with obesity, type 2 diabetes and Prader Willi syndrome, with 13% weight loss over 26 weeks in patients with diabetes [101–105]. However, adverse events of venous thromboembolism including two fatal pulmonary emboli in patients with Prader Willi syndrome led to the demise of the development of beloranib [102]. ZGN-1061 (Zafgen) was developed with an improved safety profile and similar metabolic efficacy as ZGN-440, and in rodent models, it had an enhanced safety profile with similar efficacy [106]. A Phase II study of ZGN-1061 was initiated (NCT03254368, ClinicalTrials.gov); however, the FDA has placed a clinical hold on the further development of ZGN-1061. The obesity medications in the pipeline, their mechanisms of action, stage of development, and sponsor are presented in Table 1.
Therapeutic targets for the treatment of microsporidiosis in humans
Published in Expert Opinion on Therapeutic Targets, 2018
Methionine aminopeptidase (MetAPs) activity is essential for eukaryotic cell survival as the removal of the terminal methionine of a protein is often critical for its function and post-translational modification. Two major classes of MetAPs, designated type 1 and type 2 (MetAP1 and MetAP2), were originally identified as cytosolic proteins in eukaryotes [134–136]. In the genome of the cyanobacterium, Synechocystis sp., a novel MetAP3 gene was also identified [137]. MetAP2, as a member of the dimetallohydrolase family, is a cytosolic metalloenzyme that catalyzes the hydrolytic removal of N-terminal methionine residues from nascent proteins [138–140]. Important functions of this enzyme, which is found in all organisms, are its role in tissue repair and protein degradation, as well as the role it plays in angiogenesis [139,141]. The MetAP2 genes were identified from the human pathogenic microsporidia Enc. intestinalis, Enc. hellem, Enc. cuniculi, Ent. bieneusi, and A. algerae using the strategy of homology cloning by polymerase chain reaction [142–144]. Based on genome sequence data (Microsporidiadb.org), microsporidia appear to only contain MetAP2 [145]. Since both MetAP1 and MetAP2 genes exist in mammalian genomes and the functions of these two MetAP genes overlap, this makes microsporidia MetAP2 an essential gene in microsporidia and a logical target for designing therapeutic agents for microsporidiosis [144].
Evolving multidimensional pharmacological approaches to CNV therapy in AMD
Published in Current Eye Research, 2018
As an alternative approach, we, among others, have been investigating the strategy of inhibiting a more dominant, downstream, and multifactorial etiology of endothelial cell division.33 One of the attractive targets in that regard is MetAp2, an intracellular enzyme that is recognized to directly participate in cellular protein synthesis and is overexpressed in proliferating endothelial cells.33 TNP-470, one of the most potent MetAp2 inhibitors, is a synthetic analogue of fumagillin, a natural fungal product that was characterized as an angiogenic antagonist in the Folkman laboratory.33 Recently, it was further demonstrated that a polymer formulation of TNP-470, as a MetAp2 inhibitor, was superior to a VEGF blocker, in that only the former could actually lead to the regression of the CNV size in mice. When established CNV lesions were treated with an anti-VEGF agent, there was only stabilization of the size of the CNV lesion. However, when TNP-470 was given at the same time interval, the same original CNV lesion actually decreased in size by 45%.89 Furthermore, the same formulation was shown to be a broad spectrum anti-angiogenic and anti-inflammatory formulation that decisively suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2), IL-6, and TNF-alpha, as well as reducing the production of F4/80+CD 45+ macrophage cells, which were not being subdued by anti-VEGF agents. These results emphasize the potential merit of intervening directly in a fundamental angiogenic pathway that affects endothelial cell division, as opposed to only blocking a specific single-growth factor.