TY - JOUR

T1 - Rational Design of alpha-helical antimicrobial peptides: DOs and DON’Ts

AU - Uggerhøj, Lars Erik

AU - Poulsen, Tanja Juul

AU - Munk, Jens K.

AU - Fredborg, M.

AU - Sondergaard, T. E.

AU - Frimodt-Møller, N.

AU - Hansen, Paul Robert

AU - Wimmer, Reinhard

PY - 2015

Y1 - 2015

N2 - Antimicrobial peptides (AMPs) are promising candidates for battling multiresistant bacteria. Despite extensive research, structure–activity relationships of AMPs are not fully understood, and there is a lack of structural data relating to AMPs in lipids. Here we present the NMR structure of anoplin (GLLKRIKTLL-NH2) in a micellar environment. A vast library of substitutions was designed and tested for antimicrobial and hemolytic activity, as well as for changes in structure and lipid interactions. This showed that improvement of antimicrobial activity without concomitant introduction of strong hemolytic activity can be achieved through subtle increases in the hydrophobicity of the hydrophobic face or through subtle increases in the polarity of the hydrophilic face of the helix, or—most efficiently—a combination of both. A set of guidelines based on the results is given, for assistance in how to modify cationic α-helical AMPs in order to control activity and selectivity. The guidelines are finally tested on a different peptide.

AB - Antimicrobial peptides (AMPs) are promising candidates for battling multiresistant bacteria. Despite extensive research, structure–activity relationships of AMPs are not fully understood, and there is a lack of structural data relating to AMPs in lipids. Here we present the NMR structure of anoplin (GLLKRIKTLL-NH2) in a micellar environment. A vast library of substitutions was designed and tested for antimicrobial and hemolytic activity, as well as for changes in structure and lipid interactions. This showed that improvement of antimicrobial activity without concomitant introduction of strong hemolytic activity can be achieved through subtle increases in the hydrophobicity of the hydrophobic face or through subtle increases in the polarity of the hydrophilic face of the helix, or—most efficiently—a combination of both. A set of guidelines based on the results is given, for assistance in how to modify cationic α-helical AMPs in order to control activity and selectivity. The guidelines are finally tested on a different peptide.

U2 - 10.1002/cbic.201402581

DO - 10.1002/cbic.201402581

M3 - Journal article

C2 - 25530580

VL - 16

SP - 242

EP - 253

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 2

ER -