Small‐molecule peptides inhibit Z α₁‐antitrypsin polymerization

Abstract

IntroductionThe ␣1-antitrypsin (AT) is the most abundant circulating protease inhibitor in plasma (1-2 mg/ml) and a prototypical member of the serpin (serine protease inhibitor) superfamily [1,2]. It is primarily synthesized by the hepatocyte and enters the lung by passive diffusion to protect the alveolar matrix from proteolysis, particularly by neutrophil elastase [1][2][3][4][5][6]. The secondary structure of active AT is composed of three ␤-sheets (A, B and C), nine ␣-helices (A-I), and a reactive centre loop (RCL) which tightly entraps neutrophil elastase and other target proteases [6][7][8] [10][11][12]. The accumulation of Z-AT polymers within the hepatocyte causes liver cirrhosis and the resultant plasma deficiency can give rise to early-onset emphysema [13][14][15][16][17]. Polymerization of other serpin variants such as those of antithrombin III, ␣1-antichymotrypsin, C1-inhibitor and neuroserpin have also been described and related to thrombosis, emphysema, angioedema and dementia, respectively [18, 19]. [18,[20][21][22][23][24] Given that protein aggregation is the origin for the pathogenesis of the liver and lung diseases associated with Z-AT, the crux of the matter is to inhibit the oligomerization process and thus prevent the intracellular accumulation of Z-AT polymers. Previous studies have shown that 11-to 13-mer synthetic peptides with homology to the RCL could anneal to the A-sheet of AT

Defining the mechanism of polymerization in the serpinopathies

“…Synthetic peptides with homology to the reactive center loop block and reverse the polymerization of Z α 1 -antitrypsin (3,10,11). An extension of the new β-hairpin model of polymerization is that polymer formation should also be blocked by peptides that include strand 5A.…”

Recent Advances in the Research and Development of Alpha-1 Proteinase Inhibitor for Therapeutic Use

“…Mainly this approach has been explored with respect to the peptides and small molecules in order to prevent the aggregation of Z mutant (e.g., Mallya et al, 2007;Chang et al 2009). In the meantime, the protein's potential for binding small ligands of pharmaceutical interest has been proposed as a promising approach that is directed at, and may ultimately enhance, currently existing 1 −PI therapies (Karnaukhova et al, 2010).…”

“…Due to the abundance of 1 −PI in human plasma and its conservative tertiary structure with hydrophobic cavities (Elliott et al, 2000;Lee et al, 2001;Parfrey et al, 2003), 1 −PI has the capacity to bind small hydrophobic molecules. This property has been explored mainly with respect to the peptides and small molecules that may prevent the aggregation of the 1 −PI Z mutant (Mahadeva et al 2002;Mallya et al, 2007;Chang et al 2009). …”

The Role of Alpha-1 Antitrypsin in Emphysema

“…Understanding the configuration of the reactive loop and interacting with -sheet A prompted the hypothesis that a 6-mer with homology to P7-2 of the RCL would specifically bind to Z-AT and so prevent polymerization and explained why the 12-mer peptide preferentially bound to M-AT (right). Reproduced and adapted from Lomas and Mahadeva, 2002;Mahadeva et al, 2002;Chang et al, 2009. …”