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Review
. 2016 Jan 19:3:211.
doi: 10.3389/fbioe.2015.00211. eCollection 2015.

Synthetic Peptides as Protein Mimics

Andrea Groß  1 , Chie Hashimoto  1 , Heinrich Sticht  2 , Jutta Eichler  1
Affiliations
Review

Synthetic Peptides as Protein Mimics

Andrea Groß et al. Front Bioeng Biotechnol. .

Abstract

The design and generation of molecules capable of mimicking the binding and/or functional sites of proteins represents a promising strategy for the exploration and modulation of protein function through controlled interference with the underlying molecular interactions. Synthetic peptides have proven an excellent type of molecule for the mimicry of protein sites because such peptides can be generated as exact copies of protein fragments, as well as in diverse chemical modifications, which includes the incorporation of a large range of non-proteinogenic amino acids as well as the modification of the peptide backbone. Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their utility for biological applications. This article reviews recent advances by this and other laboratories in the use of synthetic protein mimics to modulate protein function, as well as to provide building blocks for synthetic biology.

Keywords: biomaterials; peptides; protein mimics; protein–protein interactions; structure-based design.

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Figures

Figure 1
Figure 1
Types of protein-binding sites illustrated by the HIV-1 envelope protein gp120. (A) Continuous epitope of gp120 for an antibody [pdb 4TVP (Pancera et al., 2014)]. The epitope (V3-loop tip, pink) is located in a single sequence stretch and can be reproduced in a single peptide. (B) Discontinuous protein-binding site of gp120 for its receptor CD4 [pdb 4TVP (Pancera et al., 2014)]. The binding site is located in three sequentially discontinuous segments of the protein sequence (yellow, green, and red). In a mimetic peptides, these three fragments are presented through a molecular scaffold.
Figure 2
Figure 2
Building blocks for chemical peptide synthesis. (A) Amino acid derivatives with modified backbone length and side-chain orientation. (B) Amino acid derivatives with modified aromatic side chains. (C) Scaffolds for multivalent or discontinuous peptide presentation.
Figure 3
Figure 3
Stimuli responsive peptides. (A) Transition of azobenzene (trans/cis)-derivatized helical peptides upon to light stimulus (Beharry and Woolley, 2011). (B) Transition of a random coil peptide upon temperature stimulus (Pochan et al., 2003).
Figure 4
Figure 4
Peptide mimics of the CD4-binding site of gp120. (A) X-ray structure of gp120 in the CD4-bound conformation [1GC1 (Kwong et al., 1998)]. Highlighted in orange, blue, and green are the fragments forming the discontinuous CD4 binding site. (B) CD4bs-M (Franke et al., 2007). (C) CD4-binding site mimic with triazacyclophane scaffold (Chamorro et al., 2009).
Figure 5
Figure 5
Peptide mimics of turn structures. (A) X-ray structure of gp120 [pdb 4TVP (Pancera et al., 2014)] with highlighted V3-loop (green). (B) NMR structure of protegrin 1 from porcine leukocytes [pdb 1PG1 (Fahrner et al., 1996)]. (C) V3-loop mimic, stabilized via d-Proline and l-Proline (Riedel et al., 2011).(D) Protegrin 1 mimic (L27-11), stabilized via d-Proline and l-Proline (Srinivas et al., 2010).
Figure 6
Figure 6
Trimeric presentation of a b12 mimotope in conjunction with a T-helper cell epitope (Schellinger et al., 2011).
Figure 7
Figure 7
Peptide mimics of HIV-1 gp41. Structural rearrangements in the gp41 NHR and CHR core region during transition of the pre-hairpin intermediate to the six-helix bundle [pdb 1SZT (Tan et al., 1997)], which can be inhibited through peptides.
Figure 8
Figure 8
Peptide mimics of cellular receptors. (A) CXCR4 [pdb 3ODU (Wu et al., 2010)]. The extracellular loops (highlighted in green, red, and purple) are presented by the mimetic peptide CX4-M1 (Möbius et al., 2012). (B) GPCR CRF1 [pdb 4K5Y (Hollenstein et al., 2013)] and NMR structure of its N-terminus [pdb 2L27 (Grace et al., 2010)]. The extracellular loops are highlighted in orange, red, and green. The N-terminus is depicted in blue. These sequence stretches are presented in the CRF1 mimetic peptide (Pritz et al., 2008).
Figure 9
Figure 9
Peptide mimics of an anti-inflammatory protein. Left: NMR structure of the chemotaxis inhibitory protein of S. aureus [CHIPS31-121 pdb 1XEE (Haas et al., 2005)] with highlighted discontinuous binding site for the C5a receptor, which was mimicked through the peptide CHOPS (Bunschoten et al., 2011) (right).
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