TY - JOUR
T1 - Design, synthesis, and biological evaluation of stable β6.3-Helices
T2 - Discovery of non-hemolytic antibacterial peptides
AU - Reddy, Damodara N.
AU - Singh, Sukrit
AU - Ho, Chris M.W.
AU - Patel, Janki
AU - Schlesinger, Paul
AU - Rodgers, Stephen
AU - Doctor, Allan
AU - Marshall, Garland R.
N1 - Funding Information:
The authors thank the Division of Biology and Biological Sciences at Washington University for a graduate fellowship (SS), the Washington University Career Center for an Undergradate Summer Internship Award (SS), a gift from Suzanne and Garland Marshall to the Department of Chemistry to support undergraduate research, and the Department of Biochemistry and Molecular Biophysics, WUSM for research support. Antimicrobial screening was performed by CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and The University of Queensland (Australia). We are grateful to Prof. Carl Frieden for providing access to his CD facility.
Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/4/10
Y1 - 2018/4/10
N2 - Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)8-NHCH2CH2OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)16-OtBu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A.
AB - Gramicidin A, a topical antibiotic made from alternating L and D amino acids, is characterized by its wide central pore; upon insertion into membranes, it forms channels that disrupts ion gradients. We present helical peptidomimetics with this characteristic wide central pore that have been designed to mimic gramicidin A channels. Mimetics were designed using molecular modeling focused on oligomers of heterochiral dipeptides of proline analogs, in particular azaproline (AzPro). Molecular Dynamics simulations in water confirmed the stability of the designed helices. A sixteen-residue Formyl-(AzPro-Pro)8-NHCH2CH2OH helix was synthesized as well as a full thirty-two residue Cbz-(AzPro-Pro)16-OtBu channels. No liposomal lysis activity was observed suggesting lack of channel formation, possibly due to inappropriate hydrogen-bonding interactions in the membrane. These peptidomimetics also did not hemolyze red blood cells, unlike gramicidin A.
KW - Antibiotic
KW - Azaproline foldamers
KW - Gramicidin
KW - Liposomes and beta-helices
KW - RBC hemolysis
UR - https://www.scopus.com/pages/publications/85042656782
U2 - 10.1016/j.ejmech.2018.02.057
DO - 10.1016/j.ejmech.2018.02.057
M3 - Article
C2 - 29501941
AN - SCOPUS:85042656782
SN - 0223-5234
VL - 149
SP - 193
EP - 210
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -