Shubh-Nisar/Recipe_Recommender: Recipe_Recommendor v2.0

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Peptide Inhibitor of Complement C1 (PIC1) Rapidly Inhibits Complement Activation after Intravascular Injection in Rats.

The complement system has been increasingly recognized to play a pivotal role in a variety of inflammatory and autoimmune diseases. Consequently, therapeutic modulators of the classical, lectin and alternative pathways of the complement system are currently in pre-clinical and clinical development. Our laboratory has identified a peptide that specifically inhibits the classical and lectin pathways of complement and is referred to as Peptide Inhibitor of Complement C1 (PIC1). In this study, we determined that the lead PIC1 variant demonstrates a salt-dependent binding to C1q, the initiator molecule of the classical pathway. Additionally, this peptide bound to the lectin pathway initiator molecule MBL as well as the ficolins H, M and L, suggesting a common mechanism of PIC1 inhibitory activity occurs via binding to the collagen-like tails of these collectin molecules. We further analyzed the effect of arginine and glutamic acid residue substitution on the complement inhibitory activity of our lead derivative in a hemolytic assay and found that the original sequence demonstrated superior inhibitory activity. To improve upon the solubility of the lead derivative, a pegylated, water soluble variant was developed, structurally characterized and demonstrated to inhibit complement activation in mouse plasma, as well as rat, non-human primate and human serum in vitro. After intravenous injection in rats, the pegylated derivative inhibited complement activation in the blood by 90% after 30 seconds, demonstrating extremely rapid function. Additionally, no adverse toxicological effects were observed in limited testing. Together these results show that PIC1 rapidly inhibits classical complement activation in vitro and in vivo and is functional for a variety of animal species, suggesting its utility in animal models of classical complement-mediated diseases

Pegylated versions of PA inhibit complement activity in a hemolytic assay.

<p>(A) Hemolytic assays using factor B-depleted serum were performed with PA dissolved in DMSO and its pegylated derivatives dissolved in water. Factor B-depleted serum was incubated with 0.77mM of each peptide and then added to sensitized sheep erythrocytes. (B) Titration of increasing amounts of PA and PA-dPEG24 in the hemolytic assay. Water and DMSO were used as vehicle controls in the presence of factor B-depleted serum. GVBS⁺⁺ is a buffer- only control. Values are the means of three independent experiments. Error bars represent the SEM.</p

PA-dPEG24 inhibits complement activation in rat serum, mouse plasma and non-human primate serum.

<p>Hemolytic assays using (A) Wistar rat serum, (B) mouse plasma and (C) cynomolgus monkey serum were performed with increasing amounts PA-dPEG24 dissolved in 100mM Na₂HPO₄ with 0.9% NaCl buffer for rat serum, 10mM Na₂HPO₄ with 0.9% NaCl for cynomolgus monkey serum and 0.9% NaCl for mouse plasma. Serum or plasma were incubated with peptide and then added to human AB erythrocytes. Values are the means of three independent experiments. Error bars represent the SEM.</p