De Novo Discovery of Cysteine Frameworks for Developing Multicyclic Peptide Libraries for Ligand Discovery

Li, Jinjing; Liu, Hongtan; Xiao, Shuling; Fan, Shihui; Cheng, Xueting; Wu, Chuanliu

doi:10.1021/jacs.3c11856

Cited by 5 publications

(4 citation statements)

References 49 publications

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“…The libraries contain peptides incorporating CPC (cysteine-proline-cysteine) motifs, [21] CPXXC (cysteine-proline-XÀ X-cysteine) motifs, [22] or a CXC and CPPC motif pair together with two additional cysteines. [23] Screening each of these phage libraries, against a variety of protein targets, produced sub-micromolar peptide binders, highlighting the role of using disulfide-directed motifs for the identification of potent peptide binders and inhibitors.…”

Section: Disulfide Bond Formationmentioning

confidence: 99%

Strategies for the Construction of Multicyclic Phage Display Libraries

Chen,

Pinnette,

Gao

2024

ChemBioChem

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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.

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Section: Disulfide Bond Formationmentioning

confidence: 99%

Strategies for the Construction of Multicyclic Phage Display Libraries

Chen,

Pinnette,

Gao

2024

ChemBioChem

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“…Wu and his team recently identified a multicyclic peptide binder to Trop2 using a phage-displayed peptide library. The cysteine-framework peptide binder exhibited a nanomolar affinity for the Trop2 antigen and demonstrated specific binding to Trop2 on the cell surface 97 . Given the advantages of peptides—namely their size and penetration properties, ease of synthesis and modification, versatility, customization, and lower immunogenicity—peptide-based imaging or therapeutic agents are promising for diagnosing and treating Trop2-positive tumors.…”

Section: Trop2-targeted Imagingmentioning

confidence: 99%

Trop2-targeted therapies in solid tumors: advances and future directions

Liu,

Ma,

et al. 2024

Theranostics

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“…Traditional phage-displayed peptide macrocycle libraries are disulfide-tethered cyclic peptides formed by cysteine oxidation at several fixed positions. 10–16 However, the disulfide bonds are easily exchanged with free sulfhydryl groups and are unstable in reducing environments. 17–19 In order to solve this problem, many chemical macrocyclization methods for phage libraries have been developed.…”

Section: Introductionmentioning

confidence: 99%