The Effect of Selective D- or Nα-Methyl Arginine Substitution on the Activity of the Proline-Rich Antimicrobial Peptide, Chex1-Arg20.
In vivopharmacokinetics studies have shown that the proline-rich antimicrobial peptide, A3-APO, which is a discontinuous dimer of the peptide, Chex1-Arg20, undergoes degradation to small fragments at positions Pro6-Arg7 and Val19-Arg20. With the aim of minimizing or abolishing this degradation, a series of Chex1-Arg20 analogs were preparedviaFmoc/tBu solid phase peptide synthesis with D-arginine or, in some cases, peptide backbone Nα-methylated arginine, substitution at these sites. All the peptides were tested for antibacterial activity against the Gram-negative bacteriumKlebsiella pneumoniae. The resulting activity of position-7 substitution of Chex1-Arg20 analogs showed that arginine-7 is a crucial residue for maintaining activity againstK. pneumoniae. However, arginine-20 substitution had a much less deleterious effect on the antibacterial activity of the peptide. Moreover, none of these peptides displayed any cytotoxicity to HEK and H-4-II-E mammalian cells. These results will aid the development of more effective and stable PrAMPsviajudicious amino acid substitutions.
Florey Institute of Neuroscience and Mental Health, University of MelbourneParkville, VIC, Australia; School of Chemistry, University of MelbourneParkville, VIC, Australia.
Wenyi
W
Li
Oral Health Cooperative Research Centre, Melbourne Dental School, University of MelbourneParkville, VIC, Australia; Bio21 Institute, University of MelbourneParkville, VIC, Australia.
Zhe
Z
Sun
Oral Health Cooperative Research Centre, Melbourne Dental School, University of MelbourneParkville, VIC, Australia; Bio21 Institute, University of MelbourneParkville, VIC, Australia.
Neil M
NM
O'Brien-Simpson
Department of Biology, Temple University Philadelphia, PA, USA.
Laszlo
L
Otvos
Oral Health Cooperative Research Centre, Melbourne Dental School, University of MelbourneParkville, VIC, Australia; Bio21 Institute, University of MelbourneParkville, VIC, Australia.
Eric C
EC
Reynolds
Florey Institute of Neuroscience and Mental Health, University of MelbourneParkville, VIC, Australia; School of Chemistry, University of MelbourneParkville, VIC, Australia.
Mohammed A
MA
Hossain
School of Chemistry, University of MelbourneParkville, VIC, Australia; Bio21 Institute, University of MelbourneParkville, VIC, Australia.
Frances
F
Separovic
Florey Institute of Neuroscience and Mental Health, University of MelbourneParkville, VIC, Australia; School of Chemistry, University of MelbourneParkville, VIC, Australia.
John D
JD
Wade
A3-APO; Chex1-Arg20; D-arginine; Gram-negative bacteria; K. pneumoniae; backbone Nα-methylation; proline-rich antimicrobial peptide