MMP Inhibitors and TAPI Quick Reference
from Peptides International

Following the pioneering work of Ondetti and Cushman on the ACE inhibitor, captopril (1), interest in other metalloproteases and especially matrix metalloproteases (MMP’s) has exploded. Most MMP inhibitors are thiols or hydroxamates and several reviews have summarized potential uses of these structures (2). In many cases, propeptide processing can be blocked by inhibiting zinc proteases, and this provides an effective, and potentially selective, approach for controlling peptide production and influencing signal transduction.

Metalloproteases include the digestive enzymes, carboxypeptidases, and several matrix metalloproteases (MMPs). Some MMPs, such as collagenase, are involved in degradation of the extracellular matrix during tissue remodeling. Tumor necrosis factor-a (TNF) is involved in the generation of inflammatory and neuropathic pain. The hydroxamic acid-based metalloprotease inhibitor TAPI-1 (TNF-a protease inhibitor) blocks cleavage of cell surface TNF (3). TAPI-0 is an analog of TAPI-1 that possesses similar efficacy in vitro. TAPI-2 is reported to inhibit both the activation-induced shedding of L-selectin from neutrophils, eosinophils, and lymphocytes and also inhibits phenylarsine oxide-induced L-selectin shedding (4).

The table below contains a listing of some MMP inhibitors, many of which were developed to prevent tumor metastasis and arthritis tissue damage. But these analogs, including "TAPI-0" (the original TNF-a protease inhibitor) were later shown to block TNF-a processing (3) and also to inhibit L-selectin action by inhibiting the formation of a key precursor protein (5).

Several of these analogs are available from Peptides International under an exclusive licensing agreement from Research Corporation Technologies (RCT) of Tucson. PI is also the sole agent for the future development of compounds covered under US patents 5,387,610 (2/7/95, with corrections 11/12/96) and 5,616,605 (4/1/97), as potential pharmaceutical candidates.   While work is proceeding on stabilized peptidomimetics as MMP inhibitors, the highly potent peptide-based analogs are also of interest for wound healing, as ophthalmic agents, and for other topical applications.

1. M. A. Ondetti, B. Rubin, D. Cushman, Science, 196, 441 (1977).
2. R. C. Newton, and C. P. Decicco, J. Med. Chem., 42, 2295 (1999).
3. K. M. Mohler, P. R. Sleath, J. N. Fitzner, D. P. Cerreti, M. Alderson, S. S. Kerwar, D. S. Torrence, C. Otten-Evans, T. Greenstreet, K. Weerawarna, S. R. Kronhelm, M. Petersen, M. Gerhart, C. J. Kozlosky, C. J. March, and R. A. Black, Nature, 370, 218 (1994).
4. T.A. Bennett, B.S. Edwards, L.A. Sklar, and S. Rogelj, J. Immunol., 164, 4120 (2000).  
5.  C. Feehan, K. Darlak, J. Kahn, B. Walcheck, A. F. Spatola, and T. K. Kishimoto, J. Biol. Chem., 271, 7019 (1996).
US Patents [5,387,610], [5,616,605] [5686,422] (11/11/97)

CODE

PRODUCT DESCRIPTION

VIAL

USD

ISN-3821-PI

5 mg

75

ISN-3831-PI

5 mg

95

ISN-3825-PI

5 mg

90

ISN-3835-PI

5 mg

110

IHN-3850-PI

1 mg
5 mg

125
495

IHN-3855-PI

1 mg
5 mg

125
495

IHN-3852-PI

1 mg
5 mg

125
495

IHN-33927-PI

D. Grobelny, I. Poncz, and R.E. Galardy, Biochemistry, 31, 7152 (1992).

5 mg 

175

For additional Fluorescence-Quenching Substrates
 

SDP-3818-PI
 

1 mg
5 mg

75
285

SDP-3816-PI
 

1 mg
5 mg

45
175

SDP-3670-PI
 

1 mg
5 mg

95
380

Please contact Peptides International for ordering information.
Peptides International, Inc.
PO Box 24658
Louisville, Kentucky 40224 USA
Phone: 502-266-8787 or 800-777-4779
Fax: 502-267-1FAX (1329)

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