Identification of the first low-molecular-weight inhibitors of matriptase-2.

Abstract

As recently discovered, matriptase-2, a type II transmembrane serine protease, plays a crucial role in body iron homeostasis by down-regulating hepcidin expression, which results in increased iron levels. Thus, matriptase-2 represents a novel target for the development of enzyme inhibitors potentially useful for the treatment of systemic iron overload (hemochromatosis). A comparative three-dimensional model of the catalytic domain of matriptase-2 was generated and utilized for structure-based virtual screening in combination with similarity searching and knowledge-based compound design. Two N-protected dipeptide amides containing a 4-amidinobenzylamide as P1 residue (compounds 1 and 3) were identified as the first small molecule inhibitors of matriptase-2 with K(i) values of 170 and 460 nM, respectively. An inhibitor of the closely related protease matriptase (compound 2, K(i) = 220 nM), with more than 50-fold selectivity over matriptase-2, was also identified.

• Authors: Mihiret Tekeste Sisay, Torsten Steinmetzer, Marit Stirnberg, Eva Maurer, Maya Hammami, Jürgen Bajorath, Michael Gütschow
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 15 Pg. 5523-35 (Aug 12 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20684597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzamidines
• Dipeptides
• Membrane Proteins
• Sulfonamides
• benzylsulfonylargininyl-proline-(4-amidinobenzyl)amide
• benzylsulfonylcyclohexylalanyl-proline-(4-amidinobenzyl)amide
• Serine Endopeptidases
• matriptase 2

Topics

• Amino Acid Sequence
• Benzamidines (chemical synthesis, chemistry, pharmacology)
• Catalytic Domain
• Cell Line
• Crystallography, X-Ray
• Dipeptides (chemical synthesis, chemistry, pharmacology)
• Humans
• Membrane Proteins (antagonists & inhibitors, chemistry, metabolism)
• Molecular Sequence Data
• Molecular Weight
• Serine Endopeptidases (chemistry, metabolism)
• Sulfonamides (chemical synthesis, chemistry, pharmacology)