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Conditional Antimicrobial Peptide Therapeutics.

Chayanon Ngambenjawong, Leslie W Chan, Heather E Fleming1

  • 1Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, United States.

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|August 18, 2022
PubMed
Summary
This summary is machine-generated.

Antimicrobial peptides (AMPs) show promise against resistance but face challenges. A new albumin-binding domain (ABD)-AMP conjugate improves delivery and safety by activating AMPs only at infection sites.

Keywords:
albuminantimicrobial peptideconditional therapeuticinfectionnanomedicineprotease

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Delivery

Background:

  • Antimicrobial peptides (AMPs) are potential antibiotic alternatives but suffer from short circulation times and toxicity.
  • The unique microenvironment of infection sites, similar to tumors, can be leveraged for targeted therapeutic activation.
  • Systemic administration of small, cationic AMPs is limited by pharmacokinetic and safety concerns.

Purpose of the Study:

  • To develop a long-circulating, conditionally activated AMP therapeutic to overcome limitations for systemic use.
  • To enhance pulmonary delivery of active AMP to infection sites while minimizing off-target exposure.
  • To improve the safety profile of AMPs through targeted activation in a mouse model of bacterial pneumonia.

Main Methods:

  • Design and synthesis of an albumin-binding domain (ABD)-AMP conjugate.
  • Evaluation of the conjugate's pharmacokinetics and biodistribution in a mouse model of bacterial pneumonia.
  • Assessment of protease-mediated activation of AMP activity within the infected tissue microenvironment.

Main Results:

  • The ABD-AMP conjugate demonstrated prolonged systemic circulation compared to unconjugated AMPs.
  • Systemic administration resulted in enhanced pulmonary delivery of active AMP.
  • Reduced AMP exposure in off-target organs led to an improved safety profile.
  • Conditional activation by proteases in infected tissues was confirmed.

Conclusions:

  • An ABD-AMP conjugate represents a viable strategy for developing long-circulating, conditionally activated AMP therapeutics.
  • This approach effectively enhances therapeutic delivery to infection sites and improves the safety margin of AMPs.
  • The presented framework can be applied to optimize other conditional therapeutics targeting specific microenvironments.