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Enterocytozoon
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
TNP-470 (a semisynthetic analogue of fumagillin), fluoroquinolone group of antibiotics, and antimitotic compounds like pancratistatin have been found to be of some use in treating infections by other microsporidian species.106
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
Synthetic analogs (TNP-470) of fumagillin include inhibitors of angiogenesis (Sin et al., 1997; Liu et al., 1998; Lefkove et al., 2007). These have been investigated to control the growth of anaplastic thyroid carcinoma (Hama et al., 1997) and Kaposi sarcoma (Dezube et al., 1998) with mixed success.
Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
TNP-470: It is a synthetic analog of fumagillin that blocks the growth of new blood vessels by inhibiting methionine aminopeptidase, an enzyme that plays a key role in endothelial cell proliferation (22). Preclinical studies support a role for TNP-470, in slowing tumor growth, but not in causing shrinkage of existing tumors (23). However, when used in combination with paclitaxel or other cytotoxic agents, tumor regression, disease stabilization, and improved survival were seen (24). TNP-470 combined with paclitaxel was evaluated in the phase-I setting in several tumor types including 16 patients with NSCLC. Overall this regimen was well tolerated, with minimal pharmacokinetic (PK) interactions between the two drugs. Mild-to-moderate subclinical neurocognitive impairment was seen, but this was reversible. Noteably, partial responses were reported in 6/16 NSCLC patients, 60% of whom had been pretreated with chemotherapy (25). The future role of this agent in the therapy of lung cancer is, however, unclear.
Therapeutic targets for the treatment of microsporidiosis in humans
Published in Expert Opinion on Therapeutic Targets, 2018
Microsporidia lack methionine aminopeptidase type 1 (MetAP1) and are, therefore, dependent on MetAP2, while mammalian cells have both enzymes. Thus, MetAP2 is an essential enzyme in the Microsporidia and new inhibitors of this pathway have significant promise as therapeutic agents for microsporidiosis. The natural product fumagillin is a selective and potent irreversible inhibitor of MetAP2, and fumagillin and its analogs, TNP-470, have shown promise in vitro and in murine models for the therapy of microsporidiosis and have been used in clinical studies for the treatment of cancer [191]. Fumagillin has a broader anti-microsporidian activity than albendazole and is active against both Ent. bieneusi and Encephaliozoonidae; however, it is not commercially available for human infection in most countries. New compounds that bind MetAP2 have been developed by the pharmaceutical industry as potential anticancer therapies. For example, beloranib (CKD-732), which is a fumagillin derivative, has a much higher anti-angiogenic activity than fumagillin and has been used in a clinical trial [192], and PPI-2458, another fumagillin derivative, has shown efficacy in rodent cancer models and has significant MetAP2 inhibitory activity [193,194]. Fumagillin analogs have been demonstrated to inhibit Enc. cuniculi in vitro and in vivo [15]. New MetAP2 inhibitors hold significant promise for the treatment of microsporidiosis.
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.