Bioactivity improvement via display of the hydrophobic core of HYD1 in a cyclic β‐hairpin‐like scaffold, MTI‐101. Issue 3 (9th October 2020)

• Record Type: Journal Article
• Authors: Jain, Priyesh; Badger, David B.; Liang, Yi; Gebhard, Anthony W.; Santiago, Daniel; Murray, Philip; Kaulagari, Sridhar R.; Gauthier, Ted J.; Nair, Rajesh; Kumar, MohanRaja; Guida, Wayne C.; Hazlehurst, Lori A.; McLaughlin, Mark L.
• Is Part Of: Peptide science. Volume 113:Issue 3(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-10-09
• Subjects: Peptides -- Periodicals; 572.6505
• DOI: 10.1002/pep2.24199
• Languages: English
• ISSNs: 2475-8817

Abstract

Abstract: HYD1 is an all D‐amino acid linear 10‐mer peptide that was discovered by one‐bead‐one‐compound screening. HYD1 has five hydrophobic amino acids flanked by polar amino acids. Alanine scanning studies showed that alternating hydrophobic amino acid residues and N‐ and C‐terminal lysine side chains were contributors to the biological activity of the linear 10‐mer analogs. This observation led us to hypothesize that display of the hydrophobic pentapeptide sequence of HYD1 in a cyclic beta‐hairpin‐like scaffold could lead to better bioavailability and biological activity. An amphipathic pentapeptide sequence was used to form an antiparallel strand and those strands were linked via dipeptide‐like sequences selected to promote β‐turns. Early cyclic analogs were more active but otherwise mimicked the biological activity of the linear HYD1 peptide. The cyclic peptidomimetics were synthesized using standard Fmoc solid phase synthesis to form linear peptides, followed by solution phase or on‐resin cyclization. SAR studies were carried out with an aim to increase the potency of these drug candidates for the killing of multiple myeloma cells in vitro . The solution structures of 1, 5, and 10 were elucidated using NMR spectroscopy. 1 H NMR and 2D TOCSY studies of these peptides revealed a downfield Hα proton chemical shift and 2D NOE spectral analysis consistent with a β‐hairpin‐like structure. Abstract :