Peptide-Based Selective Inhibitors of Matrix Metalloproteinase-Mediated Activities

Abstract

The matrix metalloproteinases (MMPs) exhibit a broad array of activities, some catalytic and some non-catalytic in nature. An overall lack of selectivity has rendered small molecule, active site targeted MMP inhibitors problematic in execution. Inhibitors that favor few or individual members of the MMP family often take advantage of interactions outside the enzyme active site. We presently focus on peptide-based MMP inhibitors and probes that do not incorporate conventional Zn2+ binding groups. In some cases, these inhibitors and probes function by binding only secondary binding sites (exosites), while others bind both exosites and the active site. A myriad of MMP mediated-activities beyond selective catalysis can be inhibited by peptides, particularly cell adhesion, proliferation, motility, and invasion. Selective MMP binding peptides comprise highly customizable, unique imaging agents. Areas of needed improvement for MMP targeting peptides include binding affinity and stability.

MMP-14 in skeletal muscle repair

“…The formation of a symmetrical homodimerized form of MMP-14 is facilitated by the peptide sequences on blades II and III (Tochowicz et al 2011). Such a sequence on blade II increases the specific association with collagen I by providing an additional interaction site for the triple-helical structure with MMP-14 outside of the catalytic site; this facilitates proper spatial arrangement of collagen I prior to its cleavage (Ndinguri et al 2012). On the other hand, the association between blades I and IV of the hemopexin domains of two MMP-14 molecules form an asymmetrical dimer (Zarrabi et al 2011).…”

“…In general, this domain facilitates various functions of MMP-14, including association with, and modification of its substrates (Nagase et al 2006;Ndinguri et al 2012;Piccard et al 2007;Takino et al 2003). The high specificity in substrate recognition by the MMP-14 hemopexin domain relies on additional loop structures (not found on other MMPs) on the outermost strand of each of the blades, each comprised of an eight-amino acid peptide sequence (Ndinguri et al 2012;Zarrabi et al 2011). The formation of a symmetrical homodimerized form of MMP-14 is facilitated by the peptide sequences on blades II and III (Tochowicz et al 2011).…”

Matrix metalloproteinases as drivers and therapeutic targets in breast cancer

“…Many such inhibitors are peptides that mimic natural substrates or that compete with binding epitopes on binding partner proteins. Although as peptides they possess challenges relating to stability that may preclude direct development as drugs, studies using these peptides as probes help to define the relevant MMP exosites, and can provide proof of principle for the concept of selectively inhibiting a subset of MMP biological activities (141). Triple helical peptides (THPs) that mimic the structure of triple helical collagen substrates, along with THP derivatives that mimic transition states in proteolysis, represent one such class of peptide inhibitors (141).…”

“…Although as peptides they possess challenges relating to stability that may preclude direct development as drugs, studies using these peptides as probes help to define the relevant MMP exosites, and can provide proof of principle for the concept of selectively inhibiting a subset of MMP biological activities (141). Triple helical peptides (THPs) that mimic the structure of triple helical collagen substrates, along with THP derivatives that mimic transition states in proteolysis, represent one such class of peptide inhibitors (141). THP substrate and transition state analogues targeting exosites on fibronectin domains along with the catalytic domain show high affinity and selectivity for MMP-2 and -9 (142), and can be designed using exosite affinity to inhibit only a subset of proteolytic activities, in one example blocking cleavage of type V collagen but not interstitial collagen (143).…”

Mechanistic investigations of matrix metalloproteinase-8 inhibition by metal abstraction peptide

“…[4][5][6][7] Although the activity of MMP-8 is naturally regulated by inhibitory proteins, dysregulation of MMP-8 has been found in a variety of disease states, and thus, development of specific small molecule and peptide-based inhibitors for these MMPs has been an active area of research. [11][12][13][14][15] MMP-8 contains a large binding pocket with a flexible loop which has hindered the development of very tight binding inhibitors. 15 It has recently been demonstrated that a small peptide containing a metal binding sequence, tether-metal abstraction peptide (MAP), grafted to dental adhesive polymer formulations, is a potent, effective inhibitor of MMP-8 activity, but the mechanism of inhibition is not known.…”