Small-molecule inhibitor: matlystatin A

Name

History: Matlystatin A was one of five matlystatins discovered as products of Actinomadura atramentaria by Ogita et al. (1992).
Peptidases inhibited: Inhibits matrix metallopeptidase-2, matrix metallopeptidase-9 (Tanzawa et al., 1992), and aminopeptidase N (Fujii et al., 1996). Matlystatin A also inhibits peptide deformylase (Madison et al., 2002).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Work with experimental models suggested that matlystatin A and the related R-94138 might inhibit tumour invasion (Fujii et al., 1996; Matsuoka et al., 2000).

CID at PubChem: 132294
Structure
Chemical/biochemical name: (2R)-2-acetamido-3-[4-[[2-[2-(hydroxycarbamoylmethyl)heptanoyl]diazinane-3-carbonyl]amino]-5-methyl-3-oxo-heptyl]sulfanyl-propanoic acid
Formula weight: 602
Related inhibitors: R-94138 (analogue from Actinomadura atramentaria: Matsuoka et al., 2000); matlystatins B, D, E, F.

Inhibitor class: This compound contains functionality of the hydroxamate class of metallopeptidase inhibitors. The first full report of hydroxamates as metallopeptidase inhibitors was that of Nishino & Powers (1978). These are reversible inhibitors in which the hydroxamic acid group forms a bidentate complex with the active site zinc. A structure (Holmes & Matthews, 1981) showed both the carbonyl oxygen and the hydroxyl oxygen close to the zinc. Specificity is achieved by fitting of other parts of the molecules to prime-side substrate-binding sites. An excellent early review of the hydroxamates as metallopeptidase inhibitors was that of Powers & Harper (1986) (pp. 244-253).