2022
DOI: 10.1021/acs.jmedchem.2c00919
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Peptide-to-Small Molecule: A Pharmacophore-Guided Small Molecule Lead Generation Strategy from High-Affinity Macrocyclic Peptides

Abstract: Recent technological innovations have led to the development of methods for the rapid identification of high-affinity macrocyclic peptides for a wide range of targets; however, it is still challenging to achieve the desired activity and membrane permeability at the same time. Here, we propose a novel small molecule lead discovery strategy, ″Peptide-to-Small Molecule″, which is a combination of rapid identification of high-affinity macrocyclic peptides via peptide display screening followed by pharmacophore-gui… Show more

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Cited by 16 publications
(16 citation statements)
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“…There are a variety of small molecules and active oligopeptides in the human body, which play great roles in metabolism and function regulation. 35,36 To explore the selectivity and anti-interference of our biosensor, some small molecules and active oligopeptides (such as Cys, GSSG, Ala-Gln, L-Car, GLU and Lys) are selected as the contrast. As observed from Fig.…”
Section: Resultsmentioning
confidence: 99%
“…There are a variety of small molecules and active oligopeptides in the human body, which play great roles in metabolism and function regulation. 35,36 To explore the selectivity and anti-interference of our biosensor, some small molecules and active oligopeptides (such as Cys, GSSG, Ala-Gln, L-Car, GLU and Lys) are selected as the contrast. As observed from Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Yoshida's group reported on the transformation of cyclic peptide to small molecules. The salient aspect of their method was making pharmacophore based on the X-ray co-crystal structure of target protein and cyclic peptide [16]. By contrast, our approach requires no structural data of the complex of target protein or cyclic peptide, such as X-ray co-crystal structures.…”
Section: Discussionmentioning
confidence: 99%
“…Similar to in vivo genetic code expansion, the FIT system is able to easily translate side chain-functionalized l -AA derivatives. Generally, tRNA AsnE2 is used, as EF-Tu affinity is not an issue, though for some bulkier npMs the optimized T stem of tRNA GluE2 may be necessary (refs , , , , , , , , , and ). In a similar manner to RaPID, the PURE system has also been combined with Mj TyrRS/tRNA opt CUA pairs for mRNA display selections by Iskandar and co-workers in 2023. , As the cotranslational incorporation of l -AA derivatives is more efficient than backbone-modifying npMs and has been extensively reviewed elsewhere, it will not be discussed in detail. ,, However, these npMs are nevertheless important and are often used in RaPID selections for their beneficial side chains.…”
Section: Applications Of Polypeptides Containing Ribosomally Translat...mentioning
confidence: 99%
“…Generally, tRNA AsnE2 and tRNA GluE2 are used to incorporate a variety of N -methyl (refs , , , , , , , , , , , , , , , , and ), linear N -alkyl, ,, branched N -alkyl, , functionalized alkyl chain (azido, alkyne, cyano, etc. ), , and cyclic N -alkyl amino acids (Figure ).…”
Section: Applications Of Polypeptides Containing Ribosomally Translat...mentioning
confidence: 99%