BPS2026 – Novel complement protein 5 inhibitors as candidate therapies for sepsis

Sepsis, a leading cause of inpatient mortality in the United States, is characterized by a dysregulated host inflammatory response. During its acute phase, aberrant activation of the complement cascade, particularly downstream of complement protein 5 (C5), induces systemic vascular permeability, coagulopathy, and multi-organ dysfunction. Although C5 is essential for host immune defense, its hyperactivation contributes significantly to sepsis pathogenesis. Consequently, selective inhibition of C5 activation by preventing its proteolytic cleavage has demonstrated therapeutic potential in sepsis animal models. The Arg751-Leu752 peptide bond, accessible and solvent-exposed, enables convertase enzymes to cleave C5 into fragments C5a and C5b. No small-molecule inhibitors of C5 activation are currently approved for sepsis, and available peptide or biologic agents tend to be prohibitively expensive, complex to manufacture, and limited in clinical use. Thus, a major unmet need remains for a cost-effective, scalable, and specific therapeutic. This project employed a computational de novo ligand design workflow using DOCK6 to generate 880 ligands. As a control, we utilized a small-molecule inhibitor (IC 50 < 0.005 μM) previously characterized by Jendza et al., which binds in the vicinity of the cleavage site but does not directly interact with residues Arg751 and Leu752. This inhibitor serves as a benchmark for binding affinity and solvent accessibility dynamics. Ligand candidates, including the control, undergo MD simulations using AMBER 24, allowing for the assessment of binding site accessibility and inhibitor binding stability over time. Preliminary results indicate that several de novo candidates exhibit binding affinities comparable to the control (−40.1 ± 0.1 kcal/mol) and demonstrate more rapid reduction in solvent exposure of the critical cleavage site. These findings suggest their potential as leads for experimental validation and development of novel modulators of complement-mediated hyperinflammation in sepsis.