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Methionine aminopeptidases: Potential therapeutic target for microsporidia and other microbes
Bhaskar C Das1,2, Parthiban Chokkalingam1, Mohammed Adil Shareef1
1Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York, USA.
Abstract:
Methionine aminopeptidases (MetAPs) have emerged as a target for medicinal chemists in the quest for novel therapeutic agents for treating cancer, obesity, and other disorders. Methionine aminopeptidase is a metalloenzyme with two structurally distinct forms in humans, MetAP-1 and MetAP-2. The MetAP2 inhibitor fumagillin, which was used as an amebicide in the 1950s, has been used for the successful treatment of microsporidiosis in humans; however, it is no longer commercially available. Despite significant efforts and investments by many pharmaceutical companies, no new MetAP inhibitors have been approved for the clinic. Several lead compounds have been designed and synthesized by researchers as potential inhibitors of MetAP and evaluated for their potential activity in a wide range of diseases. MetAP inhibitors such as fumagillin, TNP-470, beloranib, and reversible inhibitors and their analogs guide new prospects for MetAP inhibitor development in the ongoing quest for new pharmacological indications. This perspective provides insights into recent advances related to MetAP, as a potential therapeutic target in drug discovery, bioactive small molecule MetAP2 inhibitors, and data on the role of MetAP-2 as a therapeutic target for microsporidiosis.
Insights
Methionine aminopeptidases (MetAPs) are promising drug targets for cancer and obesity. While existing inhibitors show potential, developing new MetAP inhibitors for clinical use remains a challenge.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Methionine aminopeptidases (MetAPs) are metalloenzymes crucial in cellular processes, with two human forms, MetAP-1 and MetAP-2.
- MetAP2 inhibitors like fumagillin have historical therapeutic applications but are not currently available.
- Despite research, no new MetAP inhibitors have gained clinical approval, highlighting a gap in drug development.
Purpose of the Study:
- To review recent advancements in understanding Methionine aminopeptidases (MetAPs) as therapeutic targets.
- To discuss bioactive small molecule inhibitors targeting MetAP2.
- To explore the role of MetAP-2 in treating diseases like microsporidiosis.
Main Methods:
- Literature review of existing research on MetAP inhibitors.
- Analysis of drug discovery efforts and lead compounds targeting MetAPs.
- Examination of clinical and preclinical data for MetAP inhibitors.
Main Results:
- MetAPs represent a viable target class for novel therapeutic agents.
- Several small molecule inhibitors, including reversible compounds, show promise for MetAP inhibition.
- Fumagillin and its analogs, alongside TNP-470 and beloranib, provide a basis for future inhibitor design.
Conclusions:
- Continued research into MetAP inhibitors is essential for developing new treatments for various diseases.
- MetAP-2 remains a key target, particularly for infectious diseases like microsporidiosis.
- Overcoming challenges in clinical translation is critical for realizing the therapeutic potential of MetAP inhibitors.
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