Design and Structure of Peptide and Peptidomimetic Antagonists of Protein- Protein Interaction

Abstract

Peptides based on the amino acid sequences found at protein-protein interaction sites make excellent leads for antagonist development. A statistical picture of amino acids involved in protein-protein interactions indicates that proteins recognize and interact with one another through the restricted set of specialized interface amino acid residues, Pro, Ile, Tyr, Trp, Asp and Arg. These amino acids represent residues from each of the three classes of amino acids, hydrophobic, aromatic and charged, with one anionic and one cationic residue at neutral pH. The use of peptides as drug leads has been successfully used to search for antagonists of cell-surface receptors. Peptide, peptidomimetic, and non-peptide organic inhibitors of a class of cell surface receptors, the integrins, currently serve as therapeutic and diagnostic imaging agents. In this review, we discuss the structural features of protein-protein interactions as well as the design of peptides, peptidomimetics, and small organic molecules for the inhibition of protein-protein interactions. Information gained from studying inhibitors of integrin functions is now being applied to the design and testing of inhibitors of other protein-protein interactions. Most drug development progress in the past several decades has been made using the enzyme binding-pocket model of drug targets. Small molecules are designed to fit into the substrate-binding pockets of proteins based on a lock-and-key, induced-fit, or conformational ensemble model of the protein binding site. Traditionally, enzymes have been used as therapeutic drug targets because it was easier to develop rapid, sensitive screening assays, and to find low molecular weight inhibitors that blocked the active site. However, for proteins which interact with other proteins, rather than with small substrate molecules, the lack of binding pockets means that this approach will not generally succeed. There exist many diseases in which the inhibition of protein-protein interactions would provide therapeutic benefit, but there are no general methods available to address such problems. The focus of the first part of this review is to discuss the features of protein-protein interactions which may serve as general guidelines for the development and design of inhibitors for protein-protein interactions. In the second part we focus on the design of peptides (lead compounds) and their conversion into peptidomimetics or small organic molecules for the inhibition of protein-protein interactions. We draw examples from the important and emerging area of integrin-based cell adhesion and show how the principles of protein-protein interactions are followed in the discovery, optimization and usage of specific protein interface peptides as drug leads.

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

“…Peptides (Ͻ50 aa) represent a prime source for the discovery of inhibitors of protein-protein interactions as a result of their moderate size and structural diversity. Furthermore, recent progress in the development of peptide drugs has addressed many of the shortcomings typically associated with peptides, including peptide stability, half-life, and noninvasive delivery (32). The application of peptide phage display technology coupled with chemical optimization represents a powerful approach to target such large protein surfaces.…”

Novel p65 Binding Glucocorticoid-induced Leucine Zipper Peptide Suppresses Experimental Autoimmune Encephalomyelitis

“…A common structural theme in the interfaces of transient protein interactions is the frequent presence of proline residues. Although the function of proline is to bring the proteins together so as to make subsequent interactions probable, the adjacent residues determine the specificity (3,4). Greater than 60% of the mouse and human proteome exhibit at least one proline-rich motif (5).…”

“…Greater than 60% of the mouse and human proteome exhibit at least one proline-rich motif (5). The high preponderance of proline-rich regions in the interfaces of proteins involved in critical biological processes suggests that these motifs could represent an important group of targets for therapeutic interventions (4).…”

“…The advantages of the PP II helical structure for molecular recognition are the flexibility and orientation freedom offered by the extended conformation (3,6). A conceptually straightforward strategy to develop specific inhibitors of protein-protein interactions is the synthesis of interface peptides derived from the primary sequence of one of the protein binding partners (4). Examples of linear peptides exhibiting PP II conformation include peptides derived from the p85 subunit of PI 3-kinase, CD28-CDR-3 peptide, and protein kinase inhibitors (7)(8)(9).…”

Peptides as Drugs: Discovery and Development

“…These peptides themselves could serve as potential drugs, if problems such as affi nity, stability, delivery and specifi city can be managed. Alternatively, information about the structure of the crucial amino acids that constitute the contact site could be used as a basis to design mimetics; indeed, this strategy has been used to develop peptide ligand mimetics for integrin receptors [25] .…”