Targeted Modification of the Antimicrobial Peptide DGL13K Reveals a Naturally Optimized Sequence for Topical...

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) offer alternatives to conventional antibiotics, boasting broad-spectrum activity and reduced resistance development.
• Clinical application of AMPs is hindered by issues like proteolytic instability and mammalian cell toxicity.
• DGL13K, an all-D-amino acid peptide, exhibits stability, broad-spectrum activity, and low resistance potential.

Purpose of the Study:

• To enhance the therapeutic potential of the DGL13K peptide by increasing antimicrobial potency and reducing toxicity.
• To investigate the effects of various modifications on DGL13K's efficacy and safety profile.

Main Methods:

• Synthesis of DGL13K derivatives with amino acid substitutions, stereochemical alterations, and N-terminal functionalization (PEGylation or myristoylation).
• Evaluation of synthesized peptides for antimicrobial activity against bacteria and hemolytic activity against mammalian cells.
• Assessment of DGL13K and variants' efficacy in the presence of 50% serum to determine suitability for systemic applications.

Main Results:

• Several modifications altered bacterial specificity and reduced hemolytic activity but did not yield significant overall improvements compared to native DGL13K.
• The antibacterial efficacy of DGL13K and its derivatives was substantially inhibited by 50% serum.
• The parent DGL13K sequence demonstrated high stability, broad-spectrum efficacy, in vivo activity, low resistance profile, and a high safety margin.

Conclusions:

• The DGL13K sequence, derived from an evolutionarily selected protein, appears highly optimized.
• DGL13K is a promising therapeutic candidate for topical or localized infections, rather than systemic ones, due to serum inhibition.
• Further development efforts may not be necessary to improve DGL13K's core therapeutic properties for its intended applications.