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The stereochemical effect of SMAP-29 and SMAP-18 on bacterial selectivity, membrane interaction and anti-inflammatory

Binu Jacob1, Ganesan Rajasekaran1, Eun Young Kim1

  • 1Department of Medical Science, Graduate School, Chosun University, Gwangju, 501-759, Republic of Korea.

Amino Acids
|January 23, 2016
PubMed

Insights

Replacing sheep myeloid antimicrobial peptide-29 (SMAP-29) amino acids with D-isomers improved bacterial selectivity and anti-inflammatory activity. D-allo-Ile substitution in SMAP-29 enhanced antimicrobial agents development more effectively than D-Ile substitution.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Sheep myeloid antimicrobial peptide-29 (SMAP-29) is a cathelicidin-related antimicrobial peptide.
  • Antimicrobial peptides (AMPs) are crucial in innate immunity.
  • Investigating amino acid substitutions in AMPs can enhance their therapeutic potential.

Purpose of the Study:

  • To investigate the effects of L-to-D-amino acid substitution in SMAP-29 on bacterial selectivity, membrane interaction, and anti-inflammatory activity.
  • To evaluate the impact of D-amino acid incorporation on the antimicrobial efficacy of SMAP-18, an N-terminal fragment of SMAP-29.
  • To compare the efficacy of D-Ile and D-allo-Ile substitutions in enhancing AMP properties.

Main Methods:

  • Synthesis of D-enantiomeric and diastereomeric peptides of SMAP-29 (SMAP-29-E1, SMAP-29-E2, SMAP-29-D1, SMAP-29-D2).
  • Synthesis of D-enantiomeric peptides of SMAP-18 (SMAP-18-E1, SMAP-18-E2) and buforin-2.
  • Assays for antimicrobial activity, hemolytic activity, membrane depolarization, dye leakage, and anti-inflammatory effects on LPS-stimulated RAW 264.7 cells.

Main Results:

  • L-to-D-amino acid substitution in SMAP-29 did not alter its antimicrobial activity but reduced hemolytic activity for D-allo-Ile containing variants (SMAP-29-E2, SMAP-29-D2).
  • D-isomer substitution in SMAP-18 and buforin-2 significantly improved antimicrobial activity (2- to eightfold), likely due to enhanced protease stability.
  • SMAP-29-D1 and SMAP-29-D2 exhibited altered membrane disruption mechanisms compared to their L-amino acid counterparts and showed improved anti-inflammatory activity.

Conclusions:

  • D-allo-Ile substitution is a more effective strategy than D-Ile substitution for enhancing bacterial selectivity in D-enantiomeric and diastereomeric AMPs.
  • SMAP-29-D1 and SMAP-29-D2 demonstrate improved bacterial selectivity and anti-inflammatory activity, positioning them as promising candidates for novel antimicrobial and anti-inflammatory agents.
Keywords:
Anti-inflammatory activityBacterial selectivityL-to-D-amino acid substitutionProtease stabilitySMAP-29/SMAP-18

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