Antimicrobial peptides from marine invertebrates are known not only to act like cytotoxic agents, but they also can display some additional activities in mammalian organisms. In particular, these peptides can modulate the complement system as was described for tachyplesin, a peptide from the horseshoe crab. In this work, we investigated the influence on complement activation of the antimicrobial peptide arenicin-1 from the marine polychaete Arenicola marina. To study effects of arenicin on complement activation in human blood serum, we used hemolytic assays of two types, with antibody sensitized sheep erythrocytes and rabbit erythrocytes. Complement activation was also assessed, by the level of C3a production that was measured by ELISA. We found that the effect of arenicin depends on its concentration. At relatively low concentrations the peptide stimulates complement activation and lysis of target erythrocytes, whereas at higher concentrations arenicin acts as a complement inhibitor. A hypothetical mechanism of peptide action is proposed, suggesting its interaction with two complement proteins, C1q and C3. The results lead to the possibility of the development of new approaches for therapy of diseases connected with complement dysregulation, using peptide regulators derived from natural antimicrobial peptides of invertebrates.

Antimicrobial peptides (AMPs) were firstly discovered as cytotoxic substances that killed bacteria. Later they were described as biologically active peptides that are able not only to kill invaders but also to modulate host immunity. In particular, it is shown that human antimicrobial peptides are able to influence the activity of different innate and adaptive immunity components, thus, obviously, they also participate in autoimmune processes. In this review we discuss the nature of human AMPs and analyze their role in such autoimmune disorders like type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and sarcoidosis. These peptides were shown to have a “double-sided” influence on the autoimmune disease pathogenesis. Thus, described facts should be taken into account for the development of new pharmaceutical agents to cure patients with autoimmune disorders. These agents could derive from natural antimicrobial peptides that in some cases modulate immune response. For example, it was shown that human AMPs are able to modulate complement system dysregulation of which is known to be one of the most dangerous pathogenic factors during autoimmune processes.

The use of biomaterials in modern medicine has enabled advanced drug delivery strategies and led to reduced morbidity and mortality in a variety of interventions such as transplantation or hemodialysis. However, immune-mediated reactions still present a serious complication of these applications. One of the drivers of such reactions is the complement system, a central part of humoral innate immunity that acts as a first-in-line defense system in its own right but also coordinates other host defense responses. A major regulator of the complement system is the abundant plasma protein factor H (FH), which impairs the amplification of complement responses. Previously, we could show that it is possible to recruit FH to biomedical surfaces using the phage display-derived cyclic peptide 5C6 and, consequently, reduce deposition of C3b, an activation product of the complement system. However, the optimal orientation of 5C6 on surfaces, structural determinants within the peptide for the binding, and the exact binding region on FH remained unknown. Here, we show that the cyclic core and C-terminal region of 5C6 are essential for its interaction with FH and that coating through its N-terminus strongly increases FH recruitment and reduces C3-mediated opsonization in a microparticle-based assay. Furthermore, we could demonstrate that 5C6 selectively binds to FH but not to related proteins. The observation that 5C6 also binds murine FH raises the potential for translational evaluation in animal models. This work provides important insight for the future development of 5C6 as a probe or therapeutic entity to reduce complement activation on biomaterials. STATEMENT OF SIGNIFICANCE: Biomaterials have evolved into core technologies critical to biomedical and drug delivery applications alike, yet their safe and efficient use may be adversely impacted by immune responses to the foreign materials. Taking inspiration from microbial immune evasion strategies, our group developed a peptide-based surface coating that recruits factor H (FH), a host regulator of the complement system, from plasma to the material surface and prevents unwanted activation of this innate immunity pathway. In this study, we identified the molecular determinants that define the interaction between FH and the coated peptide, developed tethering strategies with largely enhanced binding capacity and provided important insight into the target selectivity and species specificity of the FH-binding peptide, thereby paving the way for preclinical development steps.

Antimicrobial peptides (AMPs) are not only cytotoxic towards host pathogens or cancer cells but also are able to act as immunomodulators. It was shown that some human and non-human AMPs can interact with complement proteins and thereby modulate complement activity. Thus, AMPs could be considered as the base for complement-targeted therapeutics development. Arenicins from the sea polychaete Arenicola marina, the classical example of peptides with a β-hairpin structure stabilized by a disulfide bond, were shown earlier to be among the most prospective regulators. Here, we investigate the link between arenicins’ structure and their antimicrobial, hemolytic and complement-modulating activities using the derivative Ar-1-(C/A) without a disulfide bond. Despite the absence of this bond, the peptide retains all important functional activities and also appears less hemolytic in comparison with the natural forms. These findings could help to investigate new complement drugs for regulation using arenicin derivatives.

The interaction of arenicin-1, an antimicrobial peptide from the lugworm Arenicola marinawith the protein C1q of the human complement system has been analyzed using enzyme-linked receptor sorbent...