Motif mediated protein-protein interactions as drug targets

Abstract

Protein-protein interactions (PPI) are involved in virtually every cellular process and thus represent an attractive target for therapeutic interventions. A significant number of protein interactions are frequently formed between globular domains and short linear peptide motifs (DMI). Targeting these DMIs has proven challenging and classical approaches to inhibiting such interactions with small molecules have had limited success. However, recent new approaches have led to the discovery of potent inhibitors, some of them, such as Obatoclax, ABT-199, AEG-40826 and SAH-p53-8 are likely to become approved drugs. These novel inhibitors belong to a wide range of different molecule classes, ranging from small molecules to peptidomimetics and biologicals. This article reviews the main reasons for limited success in targeting PPIs, discusses how successful approaches overcome these obstacles to discovery promising inhibitors for human protein double minute 2 (HDM2), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP), and provides a summary of the promising approaches currently in development that indicate the future potential of PPI inhibitors in drug discovery.

Fig. 1

Classification of protein–protein interaction types based on affinity and stability. Stable complex (PDB: 1 F34) Structure of Ascaris pepsin inhibitor-3 bound to Porcine pepsin; Transient Domain-Domain interaction (PDB: 1AY7) Structure of the Ribonuclease SA Complex With Barstar; Transient Domain-Motif interaction (PDB: 1YCR) Structure of the MDM2 oncoprotein bound to the p53 tumour suppressor. For each complex, one of the interacting partners is displayed in blue cartoon representation, while the other is displayed in grey surface representation with the interface highlighted in red

Fig. 2

Structural comparison between a drug within Lipinski’s rules (Lisinopril), a kinase inhibitor (Imatinib) and finally a protein-protein interaction inhibitor (ABT-263). Panel a (PDB: 1O86); Crystal structure of the drug Lisinopril in complex with angiotensin-converting enzyme. Lisinopril inhibits angiotensin-converting enzyme. This drug is used to treat hypertension and symptomatic congestive heart failure, and to prevent progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy. Angiotensin-converting enzyme is represented in cartoon representation colored in grey with the active site in red. The drug is shown in licorice representation. Panel b (PDB: 2HYY); Crystal structure of the Human Abl (Abelson murine leukemia viral oncogene homolog 1) kinase domain in complex with the inhibitory drug Imatinib (licorice representation). Imatinib, Gleevec (USA), or Glivec (Europe/Australia) is a kinase inhibitor used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumours (GISTs) among other malignancies. Abl kinase domain protein surface is colored in grey with the active site in red. Imatinib is represented in licorice representation. Panel c (PDB: 4LVT); High-resolution crystal structure of the drug ABT-263 (licorice representation) bound to Bcl-2 (grey surface with interface highlighted in red). ABT-263 or Navitoclax is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins currently in clinical trials for the treatment of lymphomas and other types of cancer. Bcl-2 is shown as a grey surface, where the motif recognition interface is highlighted in red. ABT-263 is represented in licorice in the complex. A 2D representation of each drug is displayed in the lower section of the figure

Fig. 3

Targeting Protein-Protein interactions with Biologics. Panel a; Crystal structure of the complex of Smac homodimer protein with two XIAP BIR3 proteins (PDB: 1G73). The XIAP proteins are shown as a grey surface, with the motif recognition interface highlighted in red. The dimeric Smac is represented in blue cartoon representation. Next to the complex, the 2D molecular representation of the peptidomimetics of Smac in clinical trials is shown. Panel b. Structure of the Stapled p53 Peptide (SAH-p53-8) Bound to Mdm2. (PDB: 3V3B). MDM2 protein surface is displayed in grey with the motif recognition interface highlighted in red. The Stapled peptide is shown as a cartoon representation in blue and the covalent linkage is displayed in licorice representation. Panel c. Structure of the αvβ (3) integrin bound to the Arg-Asp-Gly (RGD) motif of fibrinogen. (PDB: 2VDR). The integrin surface is colored in grey, and the recognition motif interface is highlighted in red. The Fibrinogen binding motif is represented in licorice. Below the complex structure, a 2D representation of the protein-protein interaction macrocyclic inhibitor Cilengitide is shown