2013
DOI: 10.1021/ja400461h
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Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries

Abstract: Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format X(m)CX(n)CX(o)CX… Show more

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Cited by 82 publications
(78 citation statements)
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“…The LUMABS architecture should also allow the incorporation of more structurally constrained epitopes, such as cyclic epitopes, bicyclic epitopes or even small protein domains. [37][38][39][40] The conformational preorganization of cyclic peptides typically reduces the entropic penalty for target protein binding, and therefore these cyclic peptides bind with an increased affinity. [37][38][39] The scope of possible applications for LUMABS is very broad and includes diagnosis of infectious diseases and auto-immune diseases, monitoring the effectiveness of vaccination campaigns and quality control of biotechnological production of (bi)specific antibodies.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…The LUMABS architecture should also allow the incorporation of more structurally constrained epitopes, such as cyclic epitopes, bicyclic epitopes or even small protein domains. [37][38][39][40] The conformational preorganization of cyclic peptides typically reduces the entropic penalty for target protein binding, and therefore these cyclic peptides bind with an increased affinity. [37][38][39] The scope of possible applications for LUMABS is very broad and includes diagnosis of infectious diseases and auto-immune diseases, monitoring the effectiveness of vaccination campaigns and quality control of biotechnological production of (bi)specific antibodies.…”
Section: Discussionmentioning
confidence: 99%
“…[37][38][39][40] The conformational preorganization of cyclic peptides typically reduces the entropic penalty for target protein binding, and therefore these cyclic peptides bind with an increased affinity. [37][38][39] The scope of possible applications for LUMABS is very broad and includes diagnosis of infectious diseases and auto-immune diseases, monitoring the effectiveness of vaccination campaigns and quality control of biotechnological production of (bi)specific antibodies. However, we believe that LUMABS will prove particularly useful for those applications where antibody detection is presently not done, because current assay technology is too expensive, time consuming and/or technologically demanding.…”
Section: Discussionmentioning
confidence: 99%
“…In the future,a ntagonists might be developed by directing bicyclic peptides to different epitopes or by generating binderswith higherb inding affinity.O ur research group has recently developed bicyclic peptidel ibraries with substantially greaters tructurald iversity,a nd subjecting thesel ibraries to model targets has yieldedl igandst om ore epitopes andw ith higher affinities. [23][24][25] From at echnological point of view,w e were pleasedt of ind that bicyclic peptides could be generated with nanomolar affinity for as mall globularp rotein such as NRR, and that the peptides stabilized the structure of NRR. Previously,w eh ad developed bicyclic peptides predominantlyt o proteases,w hich have an inherenta ffinity for peptides in the substrate binding region.…”
Section: Discussionmentioning
confidence: 99%
“…This result is consistent with the ITC measurements ( Table 2). Interestingly, a bicyclic uPA inhibitory peptide, independently isolated from a phage-displayed library of peptides with four cysteines, [18] had a sequence (CCLGRGCENHRCL) very similar to that of 24 (CSWRGCENHAAPA) for the central residues. Moreover, X-ray crystal structure analysis showed a similar mode of inhibition for the two cases, with the centrally placed Glu residue blocking the oxyanion hole.…”
Section: Nmr Analysis Shows Multiple Conformations In Solutionmentioning
confidence: 99%
“…Moreover, X-ray crystal structure analysis showed a similar mode of inhibition for the two cases, with the centrally placed Glu residue blocking the oxyanion hole. [18] Comparison of NMR and X-ray structures…”
Section: Nmr Analysis Shows Multiple Conformations In Solutionmentioning
confidence: 99%