Abstract：
:LTX 109 is a synthetic antimicrobial peptidomimetic (SAMP) currently in clinical phase II trials for topical treatment of infections of multiresistant bacterial strains. All possible eight stereoisomers of the peptidomimetic have been synthesized and tested for antimicrobial effect, hemolysis, and hydrophobicity, revealing a strong and unusual dependence on the stereochemistry for a molecule proposed to act on a general membrane mechanism. The three-dimensional structures were assessed using nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations in aqueous solution and in phospholipid bilayers. The solution structures of the most active stereoisomers are perfectly preorganized for insertion into the membrane, whereas the less active isomers need to pay an energy penalty in order to enter the lipid bilayer. This effect is also found to be reinforced by a significantly improved water solubility of the less active isomers due to a guanidyl-π stacking that helps to solvate the hydrophobic surfaces.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Isaksson J,Brandsdal BO,Engqvist M,Flaten GE,Svendsen JS,Stensen Wdoi
10.1021/jm200450hsubject
Has Abstractpub_date
2011-08-25 00:00:00pages
5786-95issue
16eissn
0022-2623issn
1520-4804journal_volume
54pub_type
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