Molecular Evolution of Peptide Ligands with Custom-Tailored Characteristics for Targeting of Glycostructures

Niels Röckendorf, Markus Borschbach and Andreas Frey

PLOS Computational Biology, 2012, vol. 8, issue 12, 1-10

Abstract: As an advanced approach to identify suitable targeting molecules required for various diagnostic and therapeutic interventions, we developed a procedure to devise peptides with customizable features by an iterative computer-assisted optimization strategy. An evolutionary algorithm was utilized to breed peptides in silico and the “fitness” of peptides was determined in an appropriate laboratory in vitro assay. The influence of different evolutional parameters and mechanisms such as mutation rate, crossover probability, gaussian variation and fitness value scaling on the course of this artificial evolutional process was investigated. As a proof of concept peptidic ligands for a model target molecule, the cell surface glycolipid ganglioside GM1, were identified. Consensus sequences describing local fitness optima were reached from diverse sets of L- and proteolytically stable D lead peptides. Ten rounds of evolutional optimization encompassing a total of just 4400 peptides lead to an increase in affinity of the peptides towards fluorescently labeled ganglioside GM1 by a factor of 100 for L- and 400 for D-peptides. Author Summary: A clever identification procedure is crucial when peptidic ligands for diagnostic and therapeutic techniques such as in vivo imaging or drug targeting are to be developed. Here, we present a propitious and versatile approach for the discovery of peptide sequences with custom features that is based on an iterative computer-assisted optimization process. The methodology smartly combines in silico evolution with in vitro testing to quickly obtain promising peptide ligand candidates with desired properties. To validate our method in a proof of concept we tried to identify peptide sequences that can bind to a glycosidic cell membrane component. We applied the evolution process by starting out with a small population of peptide lead sequences and achieved a constant increase in affinity between the peptide candidates and their target molecule with each generation. After 10 rounds and a total number of only 4400 peptides synthesized and tested, a more than 100fold improvement in target recognition could be achieved. Since all kinds of building blocks useable in chemical solid phase peptide synthesis can in principle be employed in this evolutionary optimization process, our method should prove a most versatile approach for the optimization of peptides, peptoids and peptomers towards a preset functionality.

Date: 2012
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1002800

DOI: 10.1371/journal.pcbi.1002800

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