RRC ID 63304
Author Mihara E, Watanabe S, Bashiruddin NK, Nakamura N, Matoba K, Sano Y, Maini R, Yin Y, Sakai K, Arimori T, Matsumoto K, Suga H, Takagi J.
Title Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins.
Journal Nat Commun
Abstract Protein engineering has great potential for devising multifunctional recombinant proteins to serve as next-generation protein therapeutics, but it often requires drastic modifications of the parental protein scaffolds e.g., additional domains at the N/C-terminus or replacement of a domain by another. A discovery platform system, called RaPID (Random non-standard Peptides Integrated Discovery) system, has enabled rapid discovery of small de novo macrocyclic peptides that bind a target protein with high binding specificity and affinity. Capitalizing on the optimized binding properties of the RaPID-derived peptides, here we show that RaPID-derived pharmacophore sequences can be readily implanted into surface-exposed loops on recombinant proteins and maintain both the parental peptide binding function(s) and the host protein function. We refer to this protein engineering method as lasso-grafting and demonstrate that it can endow specific binding capacity toward various receptors into a diverse set of scaffolds that includes IgG, serum albumin, and even capsid proteins of adeno-associated virus, enabling us to rapidly formulate and produce bi-, tri-, and even tetra-specific binder molecules.
Volume 12(1)
Pages 1543
Published 2021-3-9
DOI 10.1038/s41467-021-21875-0
PII 10.1038/s41467-021-21875-0
PMID 33750839
PMC PMC7943567
MeSH Capsid Proteins / chemistry Carrier Proteins / chemistry Cell Line Dependovirus Humans Immunoglobulin G / chemistry Models, Molecular Peptides / chemistry* Peptides / pharmacology* Protein Engineering / methods* Serum Albumin / chemistry Small Molecule Libraries
IF 12.121
Resource
Human and Animal Cells Jurkat