Complement Regulators and Inhibitors in Health and Disease: A Structural Perspective

Yatime, Laure; Bajic, Goran; Schatz-Jakobsen, Janus Asbjørn; Andersen, G.R.

doi:10.1007/978-1-4939-3634-2_2

Cited by 2 publications

(2 citation statements)

References 202 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas this process is crucial for host defense upon pathogenic invasion, it has to be tightly regulated to prevent aberrant complement activation in non-infected areas and the ensuing risk of damaging healthy tissues. For this purpose, host cells express membrane-bound and soluble regulators that efficiently block the complement cascade ( 6 , 7 ). Dysregulation of the complement system, often linked to genetic deficiencies in these regulatory factors, can lead to various pathological conditions, including inflammatory and hemolytic disorders that result from an excessive C5a production and/or the targeting of host red blood cells by the MAC ( 1 , 4 , 8 , 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, more specific C5 inhibitors could be advantageous, in particular inhibitors that would preserve the TP bactericidal activity. At the moment, various drug design strategies are being considered to obtain such molecules ( 7 , 22 ). In particular, one general approach to obtain complement inhibitors consists in developing molecules that mimic the properties of complement evasion proteins secreted by pathogens in order to prevent complement activation ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Single-Domain Antibody Targeting Complement Component C5 Acts as a Selective Inhibitor of the Terminal Pathway of the Complement System and Thus Functionally Mimicks the C-Terminal Domain of the Staphylococcus aureus SSL7 Protein

et al. 2018

Self Cite

View full text Add to dashboard Cite

The complement system is an efficient anti-microbial effector mechanism. On the other hand abnormal complement activation is involved in the pathogenesis of multiple inflammatory and hemolytic diseases. As general inhibition of the complement system may jeopardize patient health due to increased susceptibility to infections, the development of pathway-specific complement therapeutics has been a long-lasting goal over the last decades. In particular, pathogen mimicry has been considered as a promising approach for the design of selective anti-complement drugs. The C-terminal domain of staphylococcal superantigen-like protein 7 (SSL7), a protein secreted by Staphylococcus aureus, was recently found to be a specific inhibitor of the terminal pathway of the complement system, providing selective inhibition of cell lysis mediated by the membrane attack complex (MAC). We describe here the selection by phage display of a humanized single-domain antibody (sdAb) mimicking the C-terminal domain of SSL7. The antibody, called sdAb_E4, binds complement C5 with an affinity in the low micromolar range. Furthermore, sdAb_E4 induces selective inhibition of MAC-mediated lysis, allowing inhibition of red blood cell hemolysis and inhibition of complement deposition on apopto-necrotic cells, while maintaining efficient bactericidal activity of the complement terminal pathway. Finally, we present preliminary results indicating that sdAb_E4 may also be efficient in inhibiting hemolysis of erythrocytes from patients with paroxysmal nocturnal hemoglobinuria. Our data provide a proof of concept for the design of a selective MAC inhibitor capable of retaining complement bacteriolytic activity and this study opens up promising perspectives for the development of an sdAb_E4-derived therapeutics with application in the treatment of complement-mediated hemolytic disorders.

show abstract