| Autor: |
Agnew HD; Indi Molecular, Inc. , 6162 Bristol Parkway , Culver City , California 90230 , United States., Coppock MB; Sensors and Electron Devices Directorate , U.S. Army Research Laboratory , Adelphi , Maryland 20783 , United States., Idso MN; Institute for Systems Biology , 401 Terry Avenue North , Seattle , Washington 98109-5234 , United States., Lai BT; Indi Molecular, Inc. , 6162 Bristol Parkway , Culver City , California 90230 , United States., Liang J; Institute for Systems Biology , 401 Terry Avenue North , Seattle , Washington 98109-5234 , United States., McCarthy-Torrens AM; Institute for Systems Biology , 401 Terry Avenue North , Seattle , Washington 98109-5234 , United States., Warren CM; Indi Molecular, Inc. , 6162 Bristol Parkway , Culver City , California 90230 , United States., Heath JR; Institute for Systems Biology , 401 Terry Avenue North , Seattle , Washington 98109-5234 , United States. |
| Abstrakt: |
Protein-catalyzed capture agents (PCCs) are synthetic and modular peptide-based affinity agents that are developed through the use of single-generation in situ click chemistry screens against large peptide libraries. In such screens, the target protein, or a synthetic epitope fragment of that protein, provides a template for selectively promoting the noncopper catalyzed azide-alkyne dipolar cycloaddition click reaction between either a library peptide and a known ligand or a library peptide and the synthetic epitope. The development of epitope-targeted PCCs was motivated by the desire to fully generalize pioneering work from the Sharpless and Finn groups in which in situ click screens were used to develop potent, divalent enzymatic inhibitors. In fact, a large degree of generality has now been achieved. Various PCCs have demonstrated utility for selective protein detection, as allosteric or direct inhibitors, as modulators of protein folding, and as tools for in vivo tumor imaging. We provide a historical context for PCCs and place them within the broader scope of biological and synthetic aptamers. The development of PCCs is presented as (i) Generation I PCCs, which are branched ligands engineered through an iterative, nonepitope-targeted process, and (ii) Generation II PCCs, which are typically developed from macrocyclic peptide libraries and are precisely epitope-targeted. We provide statistical comparisons of Generation II PCCs relative to monoclonal antibodies in which the protein target is the same. Finally, we discuss current challenges and future opportunities of PCCs. |
