AUTHOR=Li Wenyi , Sun Zhe , O'Brien-Simpson Neil M. , Otvos Laszlo , Reynolds Eric C. , Hossain Mohammed A. , Separovic Frances , Wade John D. TITLE=The Effect of Selective D- or Nα-Methyl Arginine Substitution on the Activity of the Proline-Rich Antimicrobial Peptide, Chex1-Arg20 JOURNAL=Frontiers in Chemistry VOLUME=5 YEAR=2017 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2017.00001 DOI=10.3389/fchem.2017.00001 ISSN=2296-2646 ABSTRACT=

In vivo pharmacokinetics 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 prepared via Fmoc/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 bacterium Klebsiella pneumoniae. The resulting activity of position-7 substitution of Chex1-Arg20 analogs showed that arginine-7 is a crucial residue for maintaining activity against K. 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 PrAMPs via judicious amino acid substitutions.