Title:C1-Inhibitor: Structure, Functional Diversity and Therapeutic
Development
Volume: 29
Issue: 3
Author(s): Elena Karnaukhova*
Affiliation:
- Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993,United States
Keywords:
C1-inhibitor, C1-inhibitor products, complement, contact system, hereditary angioedema, therapeutic development.
Abstract: Human C1-Inhibitor (C1INH), also known as C1-esterase inhibitor, is an important
multifunctional plasma glycoprotein that is uniquely involved in a regulatory network
of complement, contact, coagulation, and fibrinolytic systems. C1INH belongs to a
superfamily of serine proteinase inhibitors (serpins) and exhibits its inhibitory activities
towards several target proteases of plasmatic cascades, operating as a major antiinflammatory
protein in the circulation. In addition to its inhibitory activities, C1INH is
also involved in non-inhibitory interactions with some endogenous proteins, polyanions,
cells and infectious agents. While C1INH is essential for multiple physiological processes,
it is better known for its deficiency with regards to Hereditary Angioedema (HAE), a
rare autosomal dominant disease clinically manifested by recurrent acute attacks of increased
vascular permeability and edema. Since the link was first established between
functional C1INH deficiency in plasma and HAE in the 1960s, tremendous progress has
been made in the biochemical characterization of C1INH and its therapeutic development
for replacement therapies in patients with C1INH-dependent HAE. Various C1INH biological
activities, recent advances in the HAE-targeted therapies, and availability of
C1INH commercial products have prompted intensive investigation of the C1INH potential
for the treatment of clinical conditions other than HAE. This article provides an updated
overview of the structural and biological activities of C1INH, its role in HAE pathogenesis,
and recent advances in the research and therapeutic development of C1INH; it
also considers some trends for using C1INH therapeutic preparations for applications other
than angioedema, from sepsis and endotoxin shock to severe thrombotic complications
in COVID-19 patients.
