Controlled Systemic Release of Therapeutic Peptides from PEGylated Prodrugs by Serum Proteases

摘要

Bacterial infections are still the leading cause of death worldwide, with antibiotic resistance being one of the greatest pharmaceutical challenges, Media reports highlighting the threats from methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant S. aureus infections (MDR-SA) have stimulated the search for new antibiotics. Thus novel drugs against Gram-positive pathogens have entered the market during the past decade. Much less research, however, has been devoted to finding novel compounds against Gram-negative bacteria, which cause considerable concern due to the rapid spread of multidrug-resistant or extremely resistant strains. One promising class of molecules are antimicrobial peptides (AMPs), which have proven their efficacy as part of innate immunity for millions of years. As pharmaceuticals, however, AMPs have several disadvantages: a) toxic side effects observed at higher doses especially for lytic AMPs targeting the membrane, and b) the circulation time in blood, as linear peptides are degraded by blood-borne proteases and cleared rapidly by the kidneys.