Nanobodies provide insight into the molecular mechanisms of the complement cascade and offer new therapeutic strategies

TY - JOUR

T1 - Nanobodies provide insight into the molecular mechanisms of the complement cascade and offer new therapeutic strategies

AU - Zarantonello, Alessandra

AU - Pedersen, Henrik

AU - Laursen, Nick S.

AU - Andersen, Gregers R.

PY - 2021/2

Y1 - 2021/2

N2 - The complement system is part of the innate immune response, where it provides imme-diate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns of-fensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal he-moglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mecha-nistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.

AB - The complement system is part of the innate immune response, where it provides imme-diate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns of-fensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal he-moglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mecha-nistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.

KW - Complement system

KW - Convertase

KW - Inhibitor

KW - Molecular mechanism

KW - Proteolytic cascade

KW - Structural biology

UR - http://www.scopus.com/inward/record.url?scp=85101149747&partnerID=8YFLogxK

U2 - 10.3390/biom11020298

DO - 10.3390/biom11020298

M3 - Review

C2 - 33671302

AN - SCOPUS:85101149747

SN - 2218-273X

VL - 11

JO - Biomolecules

JF - Biomolecules

IS - 2

M1 - 298

ER -