MIM^TM Peptide Libraries

Premade Phage Display Peptide Libraries

The MIM™ phage display libraries are premade peptide libraries ready for screening. Based on the phage system developed by George Smith, the MIM™ libraries are easy to screen. They do not require plaque formation and don’t need a helper phage. With a pentavalent display, they mimic naive IgM and are capable of detecting binding in the micromolar range, making them one of the best tool to discover de novo peptide binders on any target

Overview

Peptide Phage Display

hage display was invented in 1985 by Nobel Prize winner George P. Smith in 1985 (1). This technique enables rapid in vitro molecular evolution by linking polypeptides fused to a bacteriophage coat protein with the encoding DNA found the bacteriophage genome. Using biopanning, a progressive enrichment process based on repeated rounds of selection, large collections of variants can be interrogated for specific properties. One of the first applications was the identification of antibody epitopes using a library of short random peptides (2). The method expanded rapidly to the discovery of novel binding peptides, peptide mimics such as streptavidin binders, identification of enzyme substrates, the discovery of potential therapeutic peptides, and many more applications. Due to their small size, peptides selected from phage libraries tend to bind biologically relevant sites on the surface of target proteins, making them an attracttive starting point for drug development (3).

hage display only requires a bench, the ability to grow E. coli in the lab, and skills in molecular biology. In such minimal settings, libraries as large as 10¹⁰ random peptides can be built and screened. Since its inception, the field has expanded with more complex library designs, introduction of cysteines to create cyclic peptides, unnatural amino acids to expand the genetic code, or post-translational modifications that alter amino acids or introduce scaffolds. Still, the method is an art full of pitfalls and traps. One of the main goals of Antibody Design Labs is to provide tools and reagents to practice this art of phage display with limited errors or downfalls.

Applications

pplications of phage display peptide libraries are multiple. Here are a few classical examples (reviewed in 3-6).

Drug discovery for the identification of biologically active peptides

• Screening for receptor agonists and antagonists

• Identification of target binding peptides

• Anti-viral/microbial peptides

• Identification of peptide mimics of non-peptide ligands

• Mirror image phage display using reverse D-polypeptides

• Agents for targeted delivery of drugs, cell-targeting, or gene delivery

Target Discovery

• In vivo panning (vascular targeting)

• Cell panning (novel targets)

• Drug target validation

Proteomics

• Mapping protein-protein interactions

Immunology

• Epitope mapping

• Development of vaccines, mimotopes

Enzymology

• Substrate phage

• Identification of enzyme substrates and inhibitors

Material

• Material-specific peptides, e.g. ice binding peptides, etc.

• Landscape libraries

Phage Systems for Peptide Display

S

everal methods and systems that achieve peptide phage display have been reported. The use of phagemids in 3+3 configuration is common. Very large libraries, above 10¹⁰ are easy to build. Unfortunately, the low valency limits discovery to peptides with relatively high affinities. Some groups prefer the use of an 8+8 system to increase the valency while staying with a phagemid system (7). Type 3 systems are the preferred method for multivalent display. The downside is the large size of the vector, which makes libraries above 10⁹ difficult to build. The very first libraries were built on derivatives of fd-tet (2). In this system, the defect in the origin of replication of the minus strand results in a colony phenotype with limited toxicity of peptide-p3 fusions (8). fADL-2blue is an ampicillin-resistant derivative of fd-tet. The MIM peptide libraries use this vector and therefore are recommended for de novo peptide discovery with affinity in the micromolar range. M13KE is a 3+3 system that is plaque-based. It has gained popularity in recent years due to the commercial availability of peptide libraries built on it. The high valency is compatible with the discovery of low affinity peptides, but the virulence of the vector and need of plaque formation enhance toxicity and limit diversity during screening campaigns.

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References

1. Smith, G.P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985, 228, 1315-1317.

2. Scott JK, Smith GP. Searching for peptide ligands with an epitope library. Science 1990, 249(4967):386-90.

3. Grøn H, Hyde-DeRuyscher R. Peptides as tools in drug discovery. Curr Opin Drug Discov Devel. 2000; 3(5):636-45.

4. Smith, G.P.; Petrenko, V.A. Phage Display. Chem. Rev. 1997, 97, 391-410.

5. Molek P, Strukelj B, Bratkovic T. Peptide phage display as a tool for drug discovery: targeting membrane receptors. Molecules. 2011 ;16(1):857-87.

6. Pitt A, Nims Z. Peptide Display Technologies. Methods Mol Biol. 2019; 2001:285-298.

7. Sidhu SS, Lowman HB, Cunningham BC, Wells JA. Phage display for selection of novel binding peptides. Methods Enzymol. 2000; 328:333-63.

8. Smith GP. Filamentous phage assembly: morphogenetically defective mutants that do not kill the host. Virology. 1988; 167(1):156-65.