Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Mar 15;474(7):1109-1125.
doi: 10.1042/BCJ20160619.

Macrocycles as protein-protein interaction inhibitors

Patrick G Dougherty  1 , Ziqing Qian  1 , Dehua Pei  2
Affiliations
Review

Macrocycles as protein-protein interaction inhibitors

Patrick G Dougherty et al. Biochem J. .

Abstract

Macrocyclic compounds such as cyclic peptides have emerged as a new and exciting class of drug candidates for inhibition of intracellular protein-protein interactions, which are challenging targets for conventional drug modalities (i.e. small molecules and proteins). Over the past decade, several complementary technologies have been developed to synthesize macrocycle libraries and screen them for binding to therapeutically relevant targets. Two different approaches have also been explored to increase the membrane permeability of cyclic peptides. In this review, we discuss these methods and their applications in the discovery of macrocyclic compounds against protein-protein interactions.

Keywords: cell-penetrating peptide; cyclic peptide; drug discovery; macrocycle; protein–protein interaction; undruggable targets.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
(A,B) Schemes showing examples of phage displayed monocyclic (A) and bicyclic peptide libraries (B). (C) Structures of macrocyclic PPI inhibitors derived from phage display libraries.
Figure 2.
Figure 2.
(A) Scheme showing the steps in the synthesis of an mRNA display peptide library. (B) Reactions involved in two different cyclization methods for mRNA display libraries. (C) Structure of a macrocyclic PPI inhibitor against E6AP derived from an mRNA display library.
Figure 3.
Figure 3.
(A) Scheme showing the generation of a SICLOPPS cyclic peptide library. (B) Structures of macrocyclic PPI inhibitors identified from SICLOPPS libraries.
Figure 4.
Figure 4.
Macrocyclic PPI inhibitors derived from DNA-encoded (A) and DOS libraries (B).
Figure 5.
Figure 5.
(A) Scheme showing the design of an OBTC monocyclic peptide library. (B) Scheme showing the design of an OBTC bicyclic peptide library. (C) Structures of representative macrocyclic PPI inhibitors obtained from OBTC libraries.
Figure 6.
Figure 6.
(A) Structure of CsA. (B) CsA exists in a closed conformation when in apolar environment and an open conformation in water.
Figure 7.
Figure 7.
Scheme showing the structure of CPP1 and the four different cargo delivery modes of cyclic CPPs.
Figure 8.
Figure 8.
Examples of cell-permeable macrocyclic inhibitors which enter cells by active transport and target intracellular proteins.
See this image and copyright information in PMC

References

    1. Venkatesan K, Rual J-F, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, et al. (2009) An empirical framework for binary interactome mapping. Nat. Methods 6, 83–90 doi: 10.1038/nmeth.1280 - DOI - PMC - PubMed
    1. Scott DE, Bayly AR, Abell C, and Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Disc 15∫, 533–550 doi: 10.1038/nrd.2016.29 - DOI - PubMed
    1. Giordanetto F, Schäfer A, and Ottmann C (2014) Stabilization of protein-protein interactions by small molecules. Drug Discov. Today: Technologies 19, 1812–1821. doi: 10.1016/j.drudis.2014.08.005 - DOI - PubMed
    1. Arkin MR, Tang Y, and Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol 21, 1102–1114 doi: 10.1016/j.chembiol.2014.09.001 - DOI - PMC - PubMed
    1. Cohen GB, Ren R, and Baltimore D (1995) Modular binding domains in signal transduction proteins. Cell 80, 237–248 doi: 10.1016/0092-8674(95)90406-9 - DOI - PubMed

Publication types

MeSH terms