Apr. 13, 2004 Torrance, Calif. (April 12, 2004) – Investigators at the Research and Education Institute (REI) at Harbor-UCLA Medical Center have identified a novel structural signature that is conserved in otherwise distinct classes of antimicrobial peptides. Antimicrobial peptides are small, naturally occurring protein antibiotics that protect organisms – including man - against infection. The discovery of such a broadly encompassing structural signature within these ancient host defense peptides could significantly accelerate development of novel molecules to fight multi-drug resistant infections.
In a research article published in the April 12 issue of the Proceedings of the National Academy of Sciences of the United States of America (PNAS), Principal Investigators Nannette Yount, PhD, and Michael Yeaman, PhD, integrated novel proteomic methods with established microbiologic techniques to reveal previously hidden structural codes common to broad classes of antimicrobial peptides from diverse organisms spanning nearly 4 billion years of evolution. Proteomics is a relatively new field of biomedical research that uses powerful computational methods to analyze molecular databases – and uncover complex structure-function codes that would otherwise remain unknown.
Using a unique combination of proteomic methods, Yount and Yeaman discovered the antimicrobial peptide signature, which integrates inverse amino acid sequence patterns and a hallmark 3-dimensional motif. This multidimensional signature is conserved in disulfide-stabilized antimicrobial peptides across biological kingdoms, and transcends motifs previously limited to defined peptide subclasses. Illustrating the promise of their findings, experimental data validating the multidimensional signature model enabled the identification of previously unrecognized antimicrobial peptides and peptide classes.
"Our work builds upon the efforts of many excellent researchers in the field. We believe this discovery offers new insights into the evolution of immune defense against infection – and drives new technology that takes advantage of the fact that antimicrobial peptides inhibit many microbial pathogens that resist conventional antibiotics," said Drs. Yount and Yeaman. "The multidimensional signature in these antimicrobial peptides provides a unifying structural code that likely reflects fundamental interactions between host and pathogen that have been taking place over profound spans of time. In addition to its potential for use in developing novel anti-infective strategies, this structural signature will facilitate the discovery of antimicrobial molecules as yet unknown, and offers a new understanding of how Nature has conserved effective molecular determinants of immune defense in diverse species, ranging from microbes to man." Yount and Yeaman are Faculty of the Division of Infectious Disease at Harbor-UCLA Medical Center, a nationally recognized teaching hospital within the Geffen School of Medicine at UCLA in Los Angeles.
Dr. Terry Smith, Investigator at the Research and Education Institute, and Chief of Molecular Medicine at Harbor-UCLA Medical Center, agrees that the potential benefits of this research are enormous. "Previous analyses distinguished antimicrobial peptides by differences in one-directional amino acid sequences, or overall secondary structures. These approaches did not uncover more comprehensive structural motifs that are conserved among diverse classes of antimicrobial peptides. The discovery of multidimensional signatures in host defense peptides by Drs. Yount and Yeamen will help to create molecules with strategic functions, potentially enabling new and effective treatments for drug-resistant infections. Moreover, it validates a new method to identify cryptic structural codes in other types of proteins that could significantly advance our ability to prevent or treat infections and non-infectious disease in man."
Citation: Proceedings of the National Academy of Sciences of the United States of America (PNAS), April 12, 2004
The Research and Education Institute at Harbor-UCLA Medical Center is one of the largest independent, not-for-profit biomedical research institutes in Los Angeles County. Affiliated with both the David Geffen School of Medicine at UCLA and the Harbor-UCLA Medical Center, the Institute has an annual budget of over $65 million and currently supports more than 1,000 research studies in areas such as cardiology, emerging infections, cancer, women's health, reproductive health, vaccine research, respiratory physiology, neonatology, molecular medicine, and genetics. REI also plays a pivotal role in the training of young physicians and scientists and is active in promoting the health and well being of communities through service programs that meet a variety of important social and public health needs.
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