Design, Synthesis, and Evaluation of Matrix Metalloprotease Inhibitors Bearing Cyclopropane-Derived Peptidomimetics as P1‘ and P2‘ Replacements

Abstract

We have previously used trisubstituted cyclopropanes as peptide replacements to induce conformational constraints in known pseudopeptide inhibitors of a number of important enzymes. Cyclopropane-derived peptide mimics are novel in that they are among the few replacements that locally orient the peptide backbone and the amino acid side chain in a predefined manner. Although these dipeptide isosteres have been employed to orient amino acid side chains mimicking the gauche(-) conformation of chi(1)-space, their ability to project the side chains into an anti orientation has not been evaluated. As a first step toward this goal, the conformationally constrained pseudopeptides 8 and 10 and their corresponding flexible analogues 9 and 11 were prepared and tested as inhibitors of matrix metalloproteinases (MMPs). These compounds are analogues of 4 and 5, which were known to be potent MMP inhibitors. The anti orientations of the isopropyl side chain in 8 and the aromatic ring in 10 relative to the peptide backbone substituents on the cyclopropane were predicted to correspond to the known orientations of the P1' and P2' side chains of 5 when bound to MMPs. Hence, 8 and 10 were designed explicitly to probe topological features of the S1' or the S2' binding pockets of the MMPs. They were also designed to explore the importance of the P1'-P2' amide group, which is known to form highly conserved hydrogen bonds in several MMP-inhibitor complexes, and the viability of introducing a retro amide linkage between P2' and P3'. Pseudopeptides 8 and 9 were found to be weak competitive inhibitors of a series of MMPs. Any entropically favorable conformational constraints that were induced by the cyclopropane in 8 were thus overwhelmed by the loss of the hydrogen bonding capability associated with the P1'-P2' amide group. On the other hand, compounds 10 and 11, which contain a P2'-P3' retro amide group, were modest competitive inhibitors of a series of MMPs. The results obtained for 10 and 11 suggest that there may be a loss of hydrogen bonding capability associated with introducing the P2'-P3' retro amide group. However, because the conformationally constrained pseudopeptide 10 was significantly more potent than its flexible analogue 11, trisubstituted cyclopropanes related to 3 may serve as useful rigid dipeptide replacements in some biologically active pseudopeptides.

What is Hidden Behind Peptide Bond Restriction and α-Carbon Asymmetry of Conserved Antigens? Peptide Bond Isosters and Chirally Transformed Pseudopeptides as Novel Elements for Synthetic Vaccines and Therapeutic Agents Against Malaria

“…(2) Most peptide bond surrogates do not greatly restrict global peptide conformation but their different influences on adjoining residues' conformational preference (and their ability to form hydrogen-bonded secondary structures) have been much studied and are frequently important [22]. (3) Strategically placed peptide bond surrogates do indeed increase their parent peptides' biological half-lives; nearly all peptide bond surrogates (with the notable exception of ester and thio-ester surrogates) are more stable regarding enzyme hydrolysis than natural peptide bonds.…”

Update 1 of: Beta-Strand Mimetics

“…Screening yielded compound 65 with a binding affinity of 11 µM, which is comparable to the Dpr peptide that binds in the same site. Potent inhibitors of the aspartic protease renin (66) 15 and MMP-1 (67) 236 have been realized using this constraint. Subsequent molecular modeling showed the compound in a similar binding mode to the -strand Dpr peptide.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…In subsequent work, we studied conformationally constrained analogues of matrix metalloprotease inhibitors, 190 Ras-farnesyltransferase inhibitors, 191 and enkephalins. 192 In each of these investigations, we never observed more than a 10-fold enhancement in potency for the constrained analogue over its more flexible control.…”