HOST DEFENSE PEPTIDES OF THE COAGULATION SYSTEM AND THEIR THERAPEUTIC POTENTIAL

Sammanfattning: Prevention and control of infectious diseases is seriously hampered by an increasing prevalence of bacteria that are resistant towards conventional antibiotics. Resistant bacteria are often the root cause of infections that trigger the complex clinical syndrome called sepsis, which is a concern for high morbidity and mortality. Despite extensive basic research and clinical studies, treatment of sepsis remains challenging due to an uncontrolled immune response mediated by various phagocytic cells, and the coagulation and complement cascades. Emerging evidence suggests that host defense peptides (HDPs) may be potential lead structures in sepsis treatment due to their ability to modulate innate immune responses as well as being directly antimicrobial. From that perspective, this thesis aimed to identify and characterize the structure-activity relationships of small HDPs derived from serine proteases. In paper I and II, structural features, governing the antimicrobial activity of peptides derived from the C-terminal region of human serine proteases were identified. Moreover the potential of these peptides to modulate inflammatory responses caused by bacterial lipopolysaccharide (LPS) was investigated. Truncated forms of thrombin-derived C-terminal peptides exhibited length- and sequence-dependent antimicrobial and immunomodulating effects in vitro and in vivo as illustrated by increasing survival rates in mouse models of LPS-induced septic shock (paper I). Quantitative structure-activity relationship (QSAR) analysis utilizing biophysical, antimicrobial and immunomodulatory activities of peptides derived from evolutionary conserved C-terminal protease domains of serine proteases, disclosed a set of active peptides with potent selective membrane disrupting effects and promising therapeutic potential in animal models of LPS-induced septic shock (paper II). The data in Paper III demonstrate generation of antimicrobial peptides from the C-terminal region of the human coagulation factor X by proteolytic cleavage with human leukocyte elastase as well as P. aeruginosa elastase. The prototypic peptide RKG25 derived from the core region of the FX protease domain, exhibited multiple biological functions including, antimicrobial, anti-inflammatory and anticoagulant effects. In summary, the findings of multiple immunomodulatory functions of these novel HDPs provides a possible new approach for the development of treatments for bacterial infections.