Potential Therapy For Human Inflammatory Disorders

Elafin: Potential Therapy for Human Inflammatory Disorders by Obiageli C. Okpala Supervisor: Dr Sukhvinder S. Bansal In partial fulfilment of the requirements for the MSc Biopharmaceuticals degree, King’s College London August 2015 Abstract Elafin is an anti-inflammatory peptide which specifically inhibits neutrophil elastase and proteinase-3 that would otherwise result in excessive inflammation and tissue damage. It has 57 amino acid residues and two functional domains; the C-terminus which is a globular whey acid protein (WAP) and the N-terminus which binds to transglutaminase enzyme. Its structure is characterised by a planar spiral shape with an exposed external loop connected by four disulphides to the internal B-sheath†¦show more content†¦It is an alarm anti-protease which is expressed locally to provide protection within tissues, against the excessive inflammatory action of these proteases (Verrier, 2012). It is encoded in humans, as trappin-2 (9.9 kDa), by a 2kb gene located on chromosome 20 (Verrier, 2012). The proteolytic cleavage of trappin-2 or pre-elafin by the enzyme tryptase, results in the release of its derivative molecule, elafin (Guyot, 2005) (Figure 2) by the loss of cementoinThe smaller pe ptide molecule would therefore have different properties from its parent molecule that would increase its effectiveness in inhibition of inflammation. This alarm anti-protease is secreted at the site of injury in response to primary cytokines like interleukin-1 (IL-1) and tumour necrosis factor (TNF), making them possibly the first line of defence in the anti-proteinase network (Sallenave, 2000). Elafin is produced mainly by epithelia in the skin, upper gastrointestinal tract, female reproductive tract, lungs and in low levels in serum. Its secretion is upregulated in the presence of inflammatory stimuli or conditions such as psoriasis and acute respiratory distress syndrome (Shaw, 2011), although some research have shown that uncontrolled protease activity may lead to its proteolytic cleavage (Small, 2015). This was confirmed in a study by Guyot et al which demonstrated that the involvement of purified NE in