Comprehensive Peptide Cyclization Examination Yields Optimized APP Scaffolds with Improved Affinity toward Mint2
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Comprehensive Peptide Cyclization Examination Yields Optimized APP Scaffolds with Improved Affinity toward Mint2. / Bartling, Christian R.O.; Alexopoulou, Flora; Kuschert, Sarah; Chin, Yanni K.Y.; Jia, Xinying; Sereikaite, Vita; Özcelik, Dennis; Jensen, Thomas M.; Jain, Palash; Nygaard, Mads M.; Harpsøe, Kasper; Gloriam, David E.; Mobli, Mehdi; Strømgaard, Kristian.
In: Journal of Medicinal Chemistry, Vol. 66, No. 4, 2023, p. 3045-3057.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Comprehensive Peptide Cyclization Examination Yields Optimized APP Scaffolds with Improved Affinity toward Mint2
AU - Bartling, Christian R.O.
AU - Alexopoulou, Flora
AU - Kuschert, Sarah
AU - Chin, Yanni K.Y.
AU - Jia, Xinying
AU - Sereikaite, Vita
AU - Özcelik, Dennis
AU - Jensen, Thomas M.
AU - Jain, Palash
AU - Nygaard, Mads M.
AU - Harpsøe, Kasper
AU - Gloriam, David E.
AU - Mobli, Mehdi
AU - Strømgaard, Kristian
N1 - Funding Information: Independent Research Fund Denmark (DFF) I Medical Sciences (grant 8020-00280B) to David E. Gloriam. Publisher Copyright: © 2023 American Chemical Society.
PY - 2023
Y1 - 2023
N2 - Peptides targeting disease-relevant protein-protein interactions are an attractive class of therapeutics covering the otherwise undruggable space between small molecules and therapeutic proteins. However, peptides generally suffer from poor metabolic stability and low membrane permeability. Hence, peptide cyclization has become a valuable approach to develop linear peptide motifs into metabolically stable and potentially cell-permeable cyclic leads. Furthermore, cyclization of side chains, also known as “stapling”, can stabilize particular secondary peptide structures. Here, we demonstrate that a comprehensive examination of cyclization strategies in terms of position, chemistry, and length is a prerequisite for the selection of optimal cyclic peptide scaffolds. Our systematic approach identifies cyclic APP dodecamer peptides targeting the phosphotyrosine binding domain of Mint2 with substantially improved affinity. We show that especially all-hydrocarbon stapling provides improved metabolic stability, a significantly stabilized secondary structure and membrane permeability.
AB - Peptides targeting disease-relevant protein-protein interactions are an attractive class of therapeutics covering the otherwise undruggable space between small molecules and therapeutic proteins. However, peptides generally suffer from poor metabolic stability and low membrane permeability. Hence, peptide cyclization has become a valuable approach to develop linear peptide motifs into metabolically stable and potentially cell-permeable cyclic leads. Furthermore, cyclization of side chains, also known as “stapling”, can stabilize particular secondary peptide structures. Here, we demonstrate that a comprehensive examination of cyclization strategies in terms of position, chemistry, and length is a prerequisite for the selection of optimal cyclic peptide scaffolds. Our systematic approach identifies cyclic APP dodecamer peptides targeting the phosphotyrosine binding domain of Mint2 with substantially improved affinity. We show that especially all-hydrocarbon stapling provides improved metabolic stability, a significantly stabilized secondary structure and membrane permeability.
U2 - 10.1021/acs.jmedchem.2c02017
DO - 10.1021/acs.jmedchem.2c02017
M3 - Journal article
C2 - 36749163
AN - SCOPUS:85147927554
VL - 66
SP - 3045
EP - 3057
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 4
ER -
ID: 337988615