Review
Protein–protein interfaces: mimics and inhibitors

https://doi.org/10.1016/S1367-5931(01)00262-9Get rights and content

Abstract

Many biological processes are mediated by specific molecular recognition between proteins. However, the thermodynamic and structural ‘rules’ for such recognition are incompletely understood, as is the potential for inhibition by small molecules. Recent progress has included the discovery of small-molecule inhibitors for several targets important in cancer.

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)

  • N.J. Skelton et al.

    Structure-function analysis of a phage display-derived peptide that binds to insulin-like growth factor binding protein 1

    Biochemistry

    (2001)
  • B.P. Orner et al.

    Toward proteomimetics: terphenyl derivatives as structural and functional mimics of extended regions of an α-helix

    J Am Chem Soc

    (2001)
  • N.J. Zondlo et al.

    Highly specific DNA recognition by a designed miniature protein

    J Am Chem Soc

    (1999)
  • J.W. Chin et al.

    Concerted evolution of structure and function in a miniature protein

    J Am Chem Soc

    (2001)
  • T.L. Blundell et al.

    X-ray analysis (1.4 Å resolution) of avian pancreatic polypeptide: small globular protein hormone

    Proc Natl Acad Sci USA

    (1981)
  • A.R. Lajmi et al.

    Minimalist, alanine-based, helical protein dimers bind to specific DNA sites

    J Am Chem Soc

    (2000)
  • A.G. Cochran et al.

    A minimal peptide scaffold for β-turn display: optimizing a strand position in disulfide-cyclized β-hairpins

    J Am Chem Soc

    (2001)
  • A.G. Cochran et al.

    Tryptophan zippers: stable monomeric β-hairpins

    Proc Natl Acad Sci USA

    (2001)
  • M.A. Blaskovich et al.

    Design of GFB-111, a platelet-derived growth factor binding molecule with antiangiogenic and anticancer activity against human tumors in mice

    Nat Biotechnol

    (2000)
  • S.M. Sebti et al.

    Design of growth factor antagonists with antiangiogenic and antitumor properties

    Oncogene

    (2000)
  • D.K. Leung et al.

    Selective disruption of protein aggregation by cyclodextrin dimers

    Proc Natl Acad Sci USA

    (2000)
  • Cited by (134)

    • Protein Surface Recognition by Synthetic Molecules

      2017, Comprehensive Supramolecular Chemistry II
    View all citing articles on Scopus
    View full text