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Protein-protein interaction modulators: advances, successes and remaining challenges

  • Lloyd Mabonga
  • Abidemi Paul KappoEmail author
Review

Abstract

Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics.

Keywords

Protein-protein interactions Small molecules Modulators Drug-like Macrocycles Small-molecule inhibitors 

Abbreviations

PPI

Protein-protein interactions

IL-2

Interleukin-2

IL-2Rα

Interleukin-2 receptor alpha chain

FBDD

Fragment-based drug discovery

FBLD

Fragment-based lead discovery

SAR

Structure-activity relationship

NMR

Nuclear magnetic resonance

Bcl-2

B cell lymphoma 2

Bcl-XL

B cell lymphoma-extra large

CS

Computational solvent

MDM2

Mouse double minute 2 homolog

HPV

Human papillomavirus

TNF

Tumour necrosis factor

TNF-α

Tumour necrosis factor alpha

TNFR1

Tumour necrosis factor receptor 1

FtsZ

Filamenting temperature-sensitive mutant Z

ZipA

Z interacting protein A

HTS

High-throughput screening

CBF

Core binding factor

DOS

Diversity-oriented synthesis

Shh

Sonic Hedgehog

Ptc1

Protein phosphatase 2C homolog 1

mTOR

Mammalian target of rapamycin

FKBP12

FK-binding protein 12

DPC

DNA-programmed chemistry

STATs

Signal transducers and activators of transcription

mAb

Monoclonal antibody

HER2

Human epidermal growth factor receptor 2

ICAM-1

Intercellular adhesion molecule-1

VEGF

Vascular endothelial growth factor

G-CSF

Granulocyte colony-stimulating factor

TPO

Thrombopoietin

LFA-1

Leukocyte integrin lymphocyte function-associated antigen 1

GPCR

G protein-coupled receptor

CCR5

C-C chemokine receptor type 5

CXCR4

C-X-C chemokine receptor type 4

CXCR7

C-X-C chemokine receptor type 7

MM

Multiple myeloma

B-CLL

B cell chronic lymphocytic leukaemia

APC

Adenomatous polyposis coli

GSK-3

Glycogen synthase kinase 3

Tcf

T cell factor

DLBCL

Diffuse large B cell lymphoma

BCL6

B cell lymphoma 6

SMRT

Silencing mediator for retinoid or thyroid-hormone receptors

HDAC3

Histone deacetylase 3

CHK1

Checkpoint kinase 1

CDKN1A

Cyclin-dependent kinase inhibitor 1

ATR

Ataxia telangiectasia and Rad3-related protein

CADD

Computer-aided drug design

AKAP

A-kinase anchoring protein

cAMP

Cyclic adenosine monophosphate

Ub

Ubiquitin

UPS

Ubiquitin proteasome system

UPP

Ubiquitin-proteasome pathway

CRL

Cullin RING E3 ligase

Ki

Inhibition constant

TRAIL

TNF-related apoptosis-inducing ligand

SCLC

Small cell lung cancer

PACs

Pancreatic acinar cells

SAHBs

Stabilised alpha-helix of Bcl-2 domains

T-ALL

T cell acute lymphoblastic leukaemia

ADAM

A disintegrin and metalloproteinase

ICN1

Intracellular domain of NOTCH1

MAML

Mastermind-like

dnMAML1

Dominant-negative fragment of MAML1

Notes

Acknowledgements

Abidemi Paul Kappo is thankful to the National Research Foundation (NRF), South Africa for a Thuthuka Grant (Grant No: 107262) award and University of Zululand Research Committee for their support. Llyod Mabonga is thankful to the Department of Science and Technology (DST) and the NRF for a Doctoral Research Bursary. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the DST, NRF and the University of Zululand.

Compliance with ethical standards

Conflict of interest

Lloyd Mabonga declares that he has no conflict of interest. Abidemi Paul Kappo declares that he has no conflict of interest.

Ethical approval

The article does not contain any studies with human participants or animals hence do not require ethics approval by the authors.

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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and MicrobiologyUniversity of ZululandKwaDlangezwaSouth Africa

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