Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives

Synthesis and evaluation of strand and turn modified ring-extended gramicidin S derivatives

Knijnenburg, A.D.
Kapoerchan, V.V.
Grotenbreg, G.M.
Spalburg, E.
de Neeling, A.J.
Mars-Groenendijk, R.H.
Noort, D.
Otero, J.M.
Llamas-Saiz, A.L.
van Raaij, M.J.
Ravensbergen, B.
Nibbering, P.H.
van der Marel, G.A.
Overkleeft, H.S.
Overhand, M.

2011

In this paper, we describe the crystal structure of previously reported ring-extended gramicidin S (GS) derivative 2 (GS14K4), containing a d-amino acid residue in one of the β-strand regions. This structure is in agreement with a previously reported modeling study of the same molecule. The polar side chain of the additional d-amino acid residue is positioned at the same face of the molecule as the hydrophobic side chains, and we believe that because of this compound 2 is considerably less hydrophobic than extended GS derivatives in which the strand regions are exclusively composed of l-amino acids. Using this backbone structure as our benchmark we prepared a small series of ring-extended GS analogues featuring sugar amino acid dipeptide isosteres of varied hydrophobicity at the turn region. We show that via this approach hydrophobicity of extended GS analogues can be tuned without affecting the secondary structure (as observed from NMR and CD spectra). Biological evaluation reveals that hydrophobicity correlates to cell toxicity, but still bacteriolysis is induced with GS analogues that are too hydrophilic to efficiently lyse human red blood cells. © 2011 Elsevier Ltd. All rights reserved.

Life
CBRN - CBRN Protection
EELS - Earth, Environmental and Life Sciences
Amphipathic peptides
Antibiotics
Cationic antimicrobial peptides
Dipeptide isostere
Gramicidin S, GS14K4
Secondary structure

http://resolver.tudelft.nl/uuid:e78ba48d-e45b-4857-ae3b-67fedf21aea2

https://doi.org/10.1016/j.bmc.2011.04.031

430116

0968-0896

Bioorganic and Medicinal Chemistry, 19 (11), 3402-3409

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