DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Development of Novel Kinocidin-Based Anti-Infective Therapeutics

Posted December 13, 2017

Michael R. Yeaman, Ph.D., Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and David Geffen School of Medicine at UCLA

Michael R. Yeaman, Ph.D., Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and David Geffen School of Medicine at UCLA
Dr. Michael R. Yeaman

Infections caused by antibiotic-resistant pathogens pose lethal threats and are increasing in both scope and frequency. Compared with the general U.S. population, U.S. military personnel face increased risk of infection by such microbes for multiple reasons. Conditions of warfare and combat injury may pose the additional risk of infection due to antibiotic-resistant organisms or infections for which vaccines are not available. Due to these conditions, U.S. military personnel face risks of superficial or penetrating wound injuries, burns, suboptimal hygiene, sleep dysregulations, heightened physical and/or emotional stress, and suboptimal nutrition—all of which further reduce immune defenses and increase vulnerability to infection. With support from a fiscal year 2011 Congressionally Directed Medical Research Programs, Defense Medical Research and Development Program, Military Infectious Disease Applied Research Award, Dr. Michael R. Yeaman at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center has developed new anti-infective therapeutics to target multidrug-resistant (MDR), Gram-negative bacteria.

His therapeutic strategy aims to circumvent the historical limitations of classical antimicrobial peptides, such as toxicity and instability, by modeling novel compounds upon kinocidins. Kinocidins are small peptides released by human platelets in immediate proximity of tissue injury or infection which exert direct antimicrobial activity and enhance immune cell capabilities to inhibit or kill pathogens. Since kinocidins are naturally active in the bloodstream, this strategy represents an advantage over traditional classes of antimicrobial peptides in terms of toxicity, possibly enabling clinical development of the lead peptides for systemic use in addition to topical use. Systemic delivery of antimicrobial peptides has been historically challenging because, upon introduction to the bloodstream, many peptides are quickly broken down into non-active components, or are toxic. Kinocidins, on the other hand, directly inhibit or kill MDR pathogens, amplify white blood cell function, work together with conventional antibiotics, and may speed wound healing. Together, these features make the technology platform and therapeutic strategy Dr. Yeaman has invented attractive to U.S. Service members who are at increased risk of microbial infection.

Dr. Yeaman has made progress in accelerating the preclinical development of his novel anti-infective and immune enhancement technology. Based on his early results, he was able to identify lead candidate peptides that can be prioritized for advancement into preclinical development. Using these novel peptides, Dr. Yeaman and his team have optimized a small-scale peptide synthesis protocol and developed a robust and efficient preclinical development program, including identification of novel mechanisms of action against high-priority pathogens. The researchers coordinated and advanced research-scale generation of peptides to enable a follow-on large-scale Good Manufacturing Practice production. This pipeline has accelerated the evaluation of novel kinocidin-based anti-infective peptides for potential clinical development. Dr. Yeaman is currently completing pharmacologic and toxicologic studies that will position the peptides closer to clinical development and commercialization, with the ultimate goal of protecting U.S. Service members against microbial threats that impact force readiness and effectiveness, and which ultimately may benefit the American public as well.



Example kinocidins and their anatomic contexts

Reference:

A patent application filed prior to Congressionally Directed Medical Research Programs funding was issued (U.S. Patent 8,569,230):
http://patft.uspto.gov/netacgi/nph-Parser?Sect2=PTO1&Sect2=HITOFF&p=1&u=/netahtml/PTO/search-bool.html&r=1&f=G&l=50&d=PALL&RefSrch=yes&Query=PN/8569230.

Link:

Public and Technical Abstracts: Development of Novel Kinocidin-Based Anti-Infective Therapeutics

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Last updated Wednesday, December 13, 2017