Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

Abstract

Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith–Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold. We developed effective synthetic protocols, both in solution and on solid supports, for iterative construction of diverse polypyrrolinones that present functionalized peptide-like side-chains. As a result of the rigid nature of the pyrrolinone scaffold, control over the backbone conformation could be exerted by modulation of the stereogenicity of the constituent monomers and the network of intramolecular hydrogen bonding. The extended conformation of the homochiral 3,5-linked polypyrrolinone scaffold proved to be an excellent mimic for β-strands and β-sheets. Application to enzyme inhibitor design and synthesis led not only to modest inhibitors of the aspartic acid protease renin and the matrix metalloprotease class of enzymes, but importantly to bioavailable HIV-1 protease inhibitors with subnanomolar binding constants. The design and synthesis of a competent peptide–pyrrolinone hybrid ligand for the class II major histocompatibility complex (MHC) antigen protein HLA-DR1 further demonstrated the utility of the 3,5-polypyrrolinone motif as a mimic for the extended polyproline type II peptide backbone. Equally important, we sought to define, by synthesis, the additional conformational space accessible to the polypyrrolinone structural motif, with the ultimate goal of accessing pyrrolinone-based turn and helix mimetics. Towards this end, a mono-N-methylated bispyrrolinone was found to adopt an extended helical array in the solid state. Subsequent synthesis of d,l-alternating (heterochiral) tetrapyrrolinones both validated the expected turn conformations in solution and led to a functionally active mimetic of a peptidal β-turn (similar to somatostatin). Finally, the design, synthesis, and structural evaluation of both acyclic and cyclic heterochiral (that is, d,l-alternating) hexapyrrolinones yielded nanotube-like assemblies in the solid state. Taken together, these results illustrate the remarkable potential of the 3,5-linked polypyrrolinone scaffold as β-strand, β-sheet, β-turn, and potentially helical peptidomimetics.

On the Terminal Homologation of Physiologically Active Peptides as a Means of Increasing Stability in Human Serum – Neurotensin, Opiorphin, B27‐KK10 Epitope, NPY

“…section (of a hemoglobin cleavage site [55]) 11 ), in a turn sub-structure (of a ribonuclease A [56]) 12 ), or in an entire amphipathic helix (of interleukin hIL-8 [57]) 13 ). With short peptides, replacement of a-by w-, i.e., b-, g-, or d-amino acid residues, is likely to destroy or significantly perturb the backbone conformation CHEMISTRY & BIODIVERSITY -Vol.…”

Strategies for the Development of Conotoxins as New Therapeutic Leads

“…Type III mimetics are non-peptidic molecules designed to mimic the spatial arrangement of key amino acid side chains in the peptide. In each case, there are many examples of successful design of peptidomimetics that have retained biological activity and significantly improved pharmacokinetic properties [24,25,26]. Key to designing such peptidomimetics is a knowledge of both the peptide pharmacophore and the peptide structure.…”

Evaluating minimalist mimics by exploring key orientations on secondary structures (EKOS)

“…Smith’s β-sheet scaffold 9 , 33 and an interface mimic 10 developed on our laboratory 34 were used as “controls” in this study. Scaffold 10 has already been shown to analog several secondary structures with a bias towards β-sheets and, relatively speaking, no notable inclination to mimic helical structures.…”