skip to main content


Search for: All records

Creators/Authors contains: "Gao, Jianmin"

Note: When clicking on a Digital Object Identifier (DOI) number, you will be taken to an external site maintained by the publisher. Some full text articles may not yet be available without a charge during the embargo (administrative interval).
What is a DOI Number?

Some links on this page may take you to non-federal websites. Their policies may differ from this site.

  1. Abstract

    Peptide therapeutics have gained great interest due to their multiple advantages over small molecule and antibody‐based drugs. Peptide drugs are easier to synthesize, have the potential for oral bioavailability, and are large enough to target protein‐protein interactions that are undruggable by small molecules. However, two major limitations have made it difficult to develop novel peptide therapeutics not derived from natural products, including the metabolic instability of peptides and the difficulty of reaching antibody‐like potencies and specificities. Compared to linear and disulfide‐monocyclized peptides, multicyclic peptides can provide increased conformational rigidity, enhanced metabolic stability, and higher potency in inhibiting protein‐protein interactions. The identification of novel multicyclic peptide binders can be difficult, however, recent advancements in the construction of multicyclic phage libraries have greatly advanced the process of identifying novel multicyclic peptide binders for therapeutically relevant protein targets. This review will describe the current approaches used to create multicyclic peptide libraries, highlighting the novel chemistries developed and the proof‐of‐concept work done on validating these libraries against different protein targets.

     
    more » « less
  2. Free, publicly-accessible full text available September 20, 2024
  3. Phage display, an ingenious invention for evaluating peptide libraries, has been limited to natural peptides that are ribosomally assembled with proteinogenic amino acids. Recently, there has been growing interest in chemically modifying phage libraries to create nonnatural cyclic and multicyclic peptides, which are appealing for use as inhibitors of protein–protein interactions. While earlier reports largely focused on side-chain side-chain cyclization, we report herein a novel strategy for creating backbone-side chain cyclized peptide libraries on phage. Our strategy capitalizes on the unique reactivity of an N-terminal cysteine (NCys) with 2-cyanobenzothiazole (CBT) which, in conjugation with another thiol-reactive group, can elicit rapid cyclization between an NCys and an internal cysteine. The resulting library was screened against two model proteins, namely Keap1 and Sortase A. The screening readily revealed potent inhibitors for both proteins with certain Keap1 ligands reaching low nanomolar potency. The backbone-side chain cyclization strategy described herein presents a significant addition to the toolkit of creating nonnatural macrocyclic peptide libraries for phage display. 
    more » « less
  4. Abstract

    Efficient and site‐specific modification of native peptides and proteins is desirable for synthesizing antibody‐drug conjugates as well as for constructing chemically modified peptide libraries using genetically encoded platforms such as phage display. In particular, there is much interest in efficient multicyclization of native peptides due to the appeals of multicyclic peptides as therapeutics. However, conventional approaches for multicyclic peptide synthesis require orthogonal protecting groups or non‐proteinogenic clickable handles. Herein, we report a cysteine‐directed proximity‐driven strategy for the constructing bicyclic peptides from simple natural peptide precursors. This linear to bicycle transformation initiates with rapid cysteine labeling, which then triggers proximity‐driven amine‐selective cyclization. This bicyclization proceeds rapidly under physiologic conditions, yielding bicyclic peptides with a Cys‐Lys‐Cys, Lys‐Cys‐Lys or N‐terminus‐Cys‐Cys stapling pattern. We demonstrate the utility and power of this strategy by constructing bicyclic peptides fused to proteins as well as to the M13 phage, paving the way to phage display of novel bicyclic peptide libraries.

     
    more » « less
  5. Abstract

    Efficient and site‐specific modification of native peptides and proteins is desirable for synthesizing antibody‐drug conjugates as well as for constructing chemically modified peptide libraries using genetically encoded platforms such as phage display. In particular, there is much interest in efficient multicyclization of native peptides due to the appeals of multicyclic peptides as therapeutics. However, conventional approaches for multicyclic peptide synthesis require orthogonal protecting groups or non‐proteinogenic clickable handles. Herein, we report a cysteine‐directed proximity‐driven strategy for the constructing bicyclic peptides from simple natural peptide precursors. This linear to bicycle transformation initiates with rapid cysteine labeling, which then triggers proximity‐driven amine‐selective cyclization. This bicyclization proceeds rapidly under physiologic conditions, yielding bicyclic peptides with a Cys‐Lys‐Cys, Lys‐Cys‐Lys or N‐terminus‐Cys‐Cys stapling pattern. We demonstrate the utility and power of this strategy by constructing bicyclic peptides fused to proteins as well as to the M13 phage, paving the way to phage display of novel bicyclic peptide libraries.

     
    more » « less
  6. Abstract

    Cysteine bioconjugation serves as a powerful tool in biological research and has been widely used for chemical modification of proteins, constructing antibody‐drug conjugates, and enabling cell imaging studies. Cysteine conjugation reactions with fast kinetics and exquisite selectivity have been under heavy pursuit as they would allow clean protein modification with just stoichiometric amounts of reagents, which minimizes side reactions, simplifies purification and broadens functional group tolerance. In this concept, we summarize the recent advances in fast cysteine bioconjugation, and discuss the mechanism and chemical principles that underlie the high efficiencies of the newly developed cysteine reactive reagents.

     
    more » « less