Abstract
Antimicrobial peptides (AMPs) are key components of innate immune systems. Because of their lasting potency, AMPs are regarded as useful candidates for developing the next generation of antimicrobials to meet the challenge of antibiotic resistance. According to CDC, 90% infections are related to the difficult-to-treat ESKAPE pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. In this lecture, I will discuss peptide design based on human cathelicidin LL-37, one of the best-studied host defense peptides. Both synthetic peptide library and structure-based design methods were utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region in 2006. However, the minimal region of LL-37 can be function-dependent. In 2014, we reported successful conversion of LL-37 into17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. The European group identified IG-24 derived P60.4 by using the peptide library approach. In 2018, they selected SAAP-148 as a candidate with a reduced binding to blood plasma. Interestingly, both 17BIPHE2 and SAAP-148 eliminated the ESKAPE pathogens and showed topical in vivo antibiofilm efficacy. In addition, a better antibiofilm outcome could be obtained when 17BIPHE2 was used in combination with traditional antibiotics. Finally, I summarize what we have learned from human LL-37 engineering. Video from the Keynote Speaker Dr. Guangshun Wang can be found: https://youtu.be/1OOpTs6Sszk
Highlights
LL-37 is overexpressed in breast, ovarian and lung cancers (Wu, Wang, Coffelt et al 2010)
Designed libraries: 1) Overlapping library; 2) Alanine scanning; Naturally occurring antimicrobial peptides (AMPs) are useful for developing novel anti-HIV peptides, and the 3) Positional library; 4) Truncation; 5) Random library; 6) Scrambled library
The engineered peptide 17BIPHE2 is most effective in this model compared to LL-37 and its native fragments
Summary
There is a great interest in developing peptide drugs. Over 60 FDA-approved peptide drugs (e.g., daptomycin, colistin); 140 under clinical trials; 500 under preclinical development. Lead identification (Novel?) Optimization in vitro (SAR) In vivo efficacy test (PK and PD); Clinical trials (Safe, effective, afforadable?) Therapeutic use/withdrawal from the market. Select antimicrobial peptides (AMPs) in practical use (red) and under development (blue). Host defense antimicrobial peptide as antibiotics: design and application strategies. There are multiple copies of genes in horse, sheep and cattle, but only one cathelicidin gene in humans. LL-37 is overexpressed in breast, ovarian and lung cancers (Wu, Wang, Coffelt et al 2010). Multiple functions of LL-37: an innate immune peptide deaths per year in USA; MRSA deaths >HIV.
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