CELA1

Chymotrypsin-like elastase family member 1 (CELA1), a serine protease involved in extracellular matrix (ECM) degradation, has emerged as a potential therapeutic target in several diseases, including pulmonary and cardiovascular diseases and cancer. CELA1 plays a critical role in tissue remodeling and inflammation, which are key processes in disease progression. Targeting CELA1 through inhibitors or modulators offers a promising approach to mitigate pathological tissue damage while preserving normal physiological functions.

NCBI Gene ID: 1990

UniProtKB ID: Q9UNI1

Structure and Function of CELA1

Proteases play essential roles in numerous physiological and pathological processes, including digestion, blood coagulation and immune response. Among them, CELA1, a member of the serine protease family, is of particular importance due to its involvement in ECM remodeling and inflammation. While physiological levels of CELA1 are necessary to maintain homeostasis, dysregulated activity is associated with various pathological conditions.

CELA1 is a member of the chymotrypsin-like serine protease family and is encoded by the CELA1 gene. It exhibits elastase activity and degrades elastin, an essential component of the ECM. The enzyme's catalytic triad of histidine, aspartate, and serine facilitates proteolysis by forming a charge relay system that activates the serine residue.

CELA1 is primarily localized to tissues with high elastin content, including the lungs, arteries and skin, where it contributes to ECM maintenance. However, excessive CELA1 activity leads to excessive elastin degradation, resulting in tissue damage and inflammation. This property makes CELA1 a double-edged sword: while essential for normal physiological processes, uncontrolled activity contributes to the pathogenesis of several diseases.

Pathophysiological Roles of CELA1

• Pulmonary Diseases: CELA1 plays a critical role in chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis by degrading elastin in the lung parenchyma, leading to reduced lung elasticity and function. Studies have shown increased expression of CELA1 in patients with COPD, suggesting its involvement in disease progression. Inhibition of CELA1 may therefore be a strategy to prevent excessive lung tissue destruction.
• Cardiovascular Disorders: Elastin degradation in arterial walls contributes to atherosclerosis and aneurysm formation. CELA1-mediated elastolysis weakens the arterial wall, increasing the risk of rupture. Targeting CELA1 activity may be beneficial in preventing aneurysm expansion and reducing vascular inflammation associated with atherosclerosis.
• Cancer Progression and Metastasis: CELA1 has been implicated in the remodeling of the tumor microenvironment, particularly in cancers where ECM degradation facilitates tumor invasion and metastasis. High CELA1 expression correlates with increased tumor aggressiveness in certain cancers. Inhibiting CELA1 could potentially limit tumor progression by preventing excessive ECM degradation and metastasis.
• Inflammatory and Autoimmune Disorders: CELA1 contributes to chronic inflammatory conditions by modulating immune responses. Excessive elastolysis generates peptides that can act as damage-associated molecular patterns (DAMPs), triggering immune activation and sustaining chronic inflammation. In diseases such as rheumatoid arthritis and inflammatory bowel disease, CELA1 inhibitors could help reduce tissue damage and inflammation.

Therapeutic Targeting of CELA1

• Antibody-Based Therapeutics: Monoclonal antibodies targeting CELA1 could offer high specificity and reduced systemic side effects. Antibody-mediated inhibition can effectively block CELA1 activity in localized disease sites while preserving systemic proteolytic functions necessary for normal physiology.
• Gene Silencing and RNA Interference (RNAi): Gene silencing techniques, such as siRNA and CRISPR-based genome editing, provide promising avenues for reducing CELA1 expression in diseases where its upregulation is pathogenic. However, challenges such as delivery efficiency and potential off-target effects need to be addressed.
• Peptide-Based Inhibitors: Peptide-based inhibitors that mimic CELA1 substrates can competitively inhibit the enzyme and prevent elastolysis. These inhibitors have shown promise in preclinical models, particularly in lung diseases where excessive elastin degradation is a primary pathological mechanism.

Vonapanitase: Recombinant Human Type I Pancreatic Elastase

Vonapanitase is a recombinant human type I pancreatic elastase (rhPE) being developed as a therapeutic agent to improve vascular access in patients undergoing hemodialysis. It is designed to degrade elastin fibers in the vascular wall, resulting in localized vascular dilation and reduced vascular resistance.

Vonapanitase selectively cleaves elastin, a key extracellular matrix protein that provides elasticity and structural integrity to blood vessels. By degrading elastin in the tunica media of arteries and veins, vonapanitase promotes outward remodeling, increasing vessel diameter and reducing the risk of vascular stenosis (narrowing). This mechanism is particularly beneficial in hemodialysis patients, where maintaining functional arteriovenous fistulas (AVFs) is critical for long-term dialysis success.

As a top supplier of therapeutic proteins, Creative BioMart offers vonapanitase, targeting CELA1. Contact us today for more information!

Reference

1. Joshi R, Heinz A, Fan Q, et al. Role of chymotrypsin-like elastase 1 in lung physiology and in α1-antitrypsin deficiency. Published online May 16, 2017. doi:10.1101/138776