TY - JOUR
T1 - Novel method to identify the optimal antimicrobial peptide in a combination matrix, using anoplin as an example
AU - Munk, Jens
AU - Ritz, Christian
AU - Fliedner, Frederikke Petrine
AU - Frimodt-Møller, Niels
AU - Hansen, Paul Robert
N1 - CURIS 2014 NEXS 044
PY - 2014
Y1 - 2014
N2 - Microbial resistance is an increasing health concern and a true danger to human wellbeing. A worldwide search for new compounds is ongoing and antimicrobial peptides are promising lead candidates for tomorrow's antibiotics. The decapeptide anoplin, GLLKRIKTLL-NH2, is an especially interesting candidate because of its small size as well as its antimicrobial and nonhemolytic properties. Optimization of the properties of an antimicrobial peptide such as anoplin requires multidimensional searching in a complex chemical space. Typically such optimization is performed by labor-intensive and costly trial and error. In this study we show the benefit of fractional factorial design for identification of the optimal antimicrobial peptide in a combination matrix. We synthesize and analyze a training set of 12 anoplin analogs, representative of 64 analogs in total. Using MIC, hemolysis and HPLC retention time data, we construct analysis of variance models that describe the relationship between these properties and structural characteristics of the analogs. We show that the mathematical models derived from the training set data can be used to predict the properties of other analogs in the chemical space. Hence, this method provides efficient identification of the optimal peptide in the searched chemical space.
AB - Microbial resistance is an increasing health concern and a true danger to human wellbeing. A worldwide search for new compounds is ongoing and antimicrobial peptides are promising lead candidates for tomorrow's antibiotics. The decapeptide anoplin, GLLKRIKTLL-NH2, is an especially interesting candidate because of its small size as well as its antimicrobial and nonhemolytic properties. Optimization of the properties of an antimicrobial peptide such as anoplin requires multidimensional searching in a complex chemical space. Typically such optimization is performed by labor-intensive and costly trial and error. In this study we show the benefit of fractional factorial design for identification of the optimal antimicrobial peptide in a combination matrix. We synthesize and analyze a training set of 12 anoplin analogs, representative of 64 analogs in total. Using MIC, hemolysis and HPLC retention time data, we construct analysis of variance models that describe the relationship between these properties and structural characteristics of the analogs. We show that the mathematical models derived from the training set data can be used to predict the properties of other analogs in the chemical space. Hence, this method provides efficient identification of the optimal peptide in the searched chemical space.
U2 - 10.1128/AAC.02369-13
DO - 10.1128/AAC.02369-13
M3 - Journal article
C2 - 24277042
VL - 58
SP - 1063
EP - 1070
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 2
ER -