Inhibition of the methionine aminopeptidase 2 enzyme for the treatment of obesity

Figures & data

Table 1 Anti-obesity drugs that are approved or in clinical trials

Drug	Mechanism of action	Comment
Approved
Orlistat^Citation79	Gastric and pancreatic lipase inhibitor	Fatty and oily stools are the major side effects
Phentermine^Citation80	Noradrenaline releaser, sympathomimetic	Only for short-term use in patients without hypertension
Lorcaserin^Citation81	5HT2C receptor agonist	Moderate efficacy with side effects like dizziness, headache, insomnia
Qsymia® (phentermine with topiramate)^Citation82	Noradrenaline releaser and anti-convulsant	Side effects include dizziness, headache, insomnia
Molecules in Phase III clinical trials
Empatic™ (bupropion with zonisamide)^Citation83	Noradrenaline/dopamine reuptake inhibitor and anti-convulsant	Side effects include nausea, headache, insomnia, anxiety
Tesofensine^Citation84	Serotonin/noradrenaline/dopamine reuptake inhibitor	Depressed mood, possibly cardiovascular side effects
Cetilistat^Citation85	Pancreatic lipase inhibitor	Side effect profile similar to orlistat
Contrave® (naltrexone sustained release/bupropion sustained release)^Citation86	Opioid receptor antagonist/noradrenaline/dopamine reuptake inhibitor	Cardiovascular side effects
Molecules in Phase II clinical trials
Beloranib^Citation87	MetAP2 inhibitor	No serious side effects reported
Velneperit^Citation88	Neuropeptide Y5 receptor antagonist	No psychiatric side effects reported
rm-493^Citation89	Selective peptide agonist for the melanocortin 4 receptor
Pramlintide^Citation90	Analog of amylin
TT-401^Citation91	Glucagon/GLP-1 dual agonist	Decreased appetite with mild nausea and vomiting
Molecules in Phase I clinical trials
PP1420^Citation92	Pancreatic polypeptide analog	No serious adverse effects reported
GSK 598809^Citation93	D3 (dopamine) antagonist	Headache, somnolence, feeling drunk, dizziness, fatigue, pain at infusion site, nausea and vomiting
ZP-2929^Citation94	Glucagon/GLP-1 dual agonist	No serious adverse effects reported

Abbreviations: GLP, glucagon-like peptide; 5HT, serotonin; MetAP, methionine aminopeptidase.

Figure 1 Chemical structures of MetAP2 inhibitors.

Abbreviation: MetAP, methionine aminopeptidase.

Figure 2 Mode of action for MetAP2 inhibitors and impact on obesity.

Note: Adapted from Zafgen.⁶³
Abbreviations: CRP, C-reactive protein; ERK, extracellular signal regulated kinase; LDL-c, low density lipoprotein-cholesterol; MetAP, methionine aminopeptidase; ROR, retinoic acid receptor-related orphan receptor; SREBP, sterol regulatory element-binding protein.

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