Staphylococcus aureus exploits host extracellular matrix components to promote tissue invasion and dissemination. Here, we identify the serine-aspartate repeat protein C (SdrC) as a previously unrecognized plasminogen-binding protein on the S. aureus surface. Using recombinant domains and isogenic mutants, we show that SdrC is a major determinant of plasminogen recruitment at the cellular level. Biochemical and biophysical analyses demonstrate that plasminogen recognition is enhanced by the cooperative action of the SdrC N2 and N3 domains, which together bind plasminogen with submicromolar to low-micromolar affinity. This interaction is lysine-dependent and is selectively inhibited by lysine and 6-aminocaproic acid, with measurable IC50 values, and requires plasminogen kringle domain 4. Importantly, SdrC-bound plasminogen remains readily activatable by host plasminogen activators, generating active plasmin capable of degrading fibrinogen. Consistently, heterologous expression of SdrC enhances plasminogen binding and promotes plasmin activity at the bacterial surface. These findings link a defined staphylococcal adhesin to localized engagement of the host fibrinolytic system and suggest that SdrC-mediated plasminogen recruitment may contribute to persistence and tissue dissemination during invasive infection. Overall, our results establish the SdrC-plasminogen axis as a mechanistically characterized and pharmacologically tractable antivirulence target.
Elisa Bellan Menegussi, A. Pellegrini, L. Acquasaliente et al.· ACS Infectious Diseases· 0 citations
Protein–protein interactions (PPIs) represent a vast and largely underexplored landscape of therapeutic targets, yet their structural features—including large, flat, and dynamic interfaces—have historically limited their druggability. In this context, cyclic peptides have emerged as a powerful class of PPI modulators, sitting at the interface between biologics and small molecules, and thus garnering key advantages of both classes. Their conformational constraint enhances binding affinity, proteolytic stability and, in some instances, cell permeability, thus enabling access to intracellular targets. This review provides an updated overview of cyclic peptides as modulators of PPIs, focusing on both conceptual foundations and practical strategies for their discovery and optimization. The main discovery approaches include natural sources, de novo design based on secondary structure mimetics, high-throughput screening, and computational approaches. Integration of these complementary strategies is crucial to enhance success rates in the discovery of effective and developable cyclic peptides. Accordingly, the present review aims to provide a practical guide for researchers entering this rapidly growing field, outlining current opportunities, methodological advances, and remaining challenges in the development of cyclic peptide-based PPI modulators.
Sara Salvi, P. Linciano, S. Collina et al.· International Journal of Mol...· 0 citations