ReviewProtein–protein interfaces: mimics and inhibitors
Introduction
The discovery of small molecules that regulate protein–protein binding interactions is of great structural interest and practical importance 1., 2.. Accordingly, the prevailing approaches have been structure-based design and combinatorial methods (selection or screening of libraries). Often, design is aimed at mimicking peptide or protein structural elements in a smaller form. A successful design may then become the scaffold for a combinatorial library. Combinatorial methods, on the other hand, allow quick evaluation of many possible ligands and frequently yield unexpected solutions. These may be structurally characterized and used as templates for further design. Some recent examples of protein minimization and mimickry are outlined below. In addition, several new reports have appeared describing particular protein–protein interactions that can be inhibited by small molecules or by very short peptides.
Section snippets
α Helices and β turns: miniproteins and novel structured mimetics
Many proteins recognize binding partners through contacts with the surface of an α helix. Because of the periodicity of the helix (3.4 residues per turn), an extended helical surface will include residues distributed over a relatively long peptide sequence. Typically, however, such a helix will not fold stably on its own, impeding the investigation of structure–function relationships. Accordingly, several methods have been developed to stabilize structure in isolated helical peptides [3],
Synthetic mimics of protein surfaces
An unusual approach to blocking protein–protein interactions has been developed by Hamilton and co-workers [2]. Four copies of a tetrapeptide loop are attached to a calixarene scaffold to create a shallow, bowl-shaped binding surface. The peptide loops are chosen to present charged or hydrophobic sidechains intended to complement the surface properties of a target protein. Application of this method to the target platelet-derived growth factor (PDGF) yielded a surprisingly potent inhibitor (IC50
Small-molecule inhibitors of MDM2–p53 complex formation
Inactivation of the p53 tumor supressor protein is implicated in a variety of cancers [17]. One mechanism of p53 inactivation is binding to the oncoprotein MDM2, which renders p53 incompetent to initiate transcription (and subsequent repair processes) in response to DNA damage. The crystal structure has been determined of the amino-terminal domain of MDM2 bound to a 15-amino-acid peptide from p53 [18]. It reveals a slightly distorted α helix from p53 binding in a hydrophobic groove on the
Small-molecule inhibitors of Bcl-2/Bcl-xL binding to pro-apoptotic Bcl-2 family members
A key mechanism for regulation of apoptosis (or programmed cell death) is the balance maintained between members of the Bcl-2 family of proteins. Several members of the family (for example Bcl-2 and Bcl-xL) inhibit apoptosis, whereas others bind to, and counteract, the effects of the inhibitory family members and are thus pro-apoptotic [21]. The NMR structure of a complex between a variant of Bcl-xL and a 16-amino-acid peptide from the pro-apoptotic family member Bak revealed the details of the
Good bets: short peptides that disrupt protein–protein interfaces
In both the MDM2–p53 and Bcl-xL–Bak systems, small-molecule discovery efforts were prompted by success in defining short peptide epitopes that could compete with the parent protein for binding. Such focused interfaces seem much more likely small-molecule targets than larger surface-area interactions. Good progress has been made with SH3 domains (small docking units present in many signal-transduction proteins). By screening small synthetic libraries, it has been possible to replace parts of the
Conclusions
Despite progress with particular systems, inhibiting protein–protein interactions with small, drug-like molecules remains, in general, extremely difficult. Nevertheless, given the importance of the problem, efforts in this direction continue. Over the past year, several promising small-molecule screening technologies have been described, any of which might be applied to protein–protein interactions. Maly et al. [39••] combine fragment screening with a simple, general linking strategy to quickly
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (43)
Antagonists of protein–protein interactions
Chem Biol
(2000)- et al.
Forming stable helical peptides using natural and artificial amino acids
Tetrahedron
(1999) Phage display in pharmaceutical biotechnology
Curr Opin Biotechnol
(2000)- et al.
Biochemical properties and biological effects of p53
Curr Opin Genet Dev
(1995) - et al.
Regulation of apoptosis in a cell-free system
Curr Biol
(1997) - et al.
Improving SH3 domain ligand selectivity using a non-natural scaffold
Chem Biol
(2000) - et al.
Analysis of PDZ domain–ligand interactions using carboxyl-terminal phage display
J Biol Chem
(2000) - et al.
Chemical ligands, genomics and drug discovery
Drug Discov Today
(2000) - et al.
Peptide and protein recognition by designed molecules
Chem Rev
(2000) - et al.
An all-hydrocarbon crosslinking system for enhancing the helicity and metabolic stability of peptides
J Am Chem Soc
(2000)
Structure-function analysis of a phage display-derived peptide that binds to insulin-like growth factor binding protein 1
Biochemistry
Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an α-helix
J Am Chem Soc
Highly specific DNA recognition by a designed miniature protein
J Am Chem Soc
Concerted evolution of structure and function in a miniature protein
J Am Chem Soc
X-ray analysis (1.4 Å resolution) of avian pancreatic polypeptide: small globular protein hormone
Proc Natl Acad Sci USA
Minimalist, alanine-based, helical protein dimers bind to specific DNA sites
J Am Chem Soc
A minimal peptide scaffold for β-turn display: optimizing a strand position in disulfide-cyclized β-hairpins
J Am Chem Soc
Tryptophan zippers: stable monomeric β-hairpins
Proc Natl Acad Sci USA
Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice
Nat Biotechnol
Design of growth factor antagonists with antiangiogenic and antitumor properties
Oncogene
Selective disruption of protein aggregation by cyclodextrin dimers
Proc Natl Acad Sci USA
Cited by (134)
Protein Surface Recognition by Synthetic Molecules
2017, Comprehensive Supramolecular Chemistry IIStructure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors
2012, European Journal of Medicinal ChemistryInhibition of VEGF transcription through blockade of the hypoxia inducible factor-1α-p300 interaction by a small molecule
2012, Bioorganic and Medicinal Chemistry LettersChemical modulators working at pharmacological interface of target proteins
2012, Bioorganic and Medicinal ChemistryDetection of retromer assembly in Plasmodium falciparum by immunosensing coupled to Surface Plasmon Resonance
2018, Biochimica et Biophysica Acta - Proteins and Proteomics