Therapeutic Targeting of Misfolding and Conformational Change in α ₁ -Antitrypsin Deficiency

Abstract

Misfolding and conformational diseases are increasing in prominence and prevalence. Both misfolding and 'postfolding' conformational mechanisms can contribute to pathogenesis and can coexist. The different contexts of folding and native state behavior may have implications for the development of therapeutic strategies. α1-antitrypsin deficiency illustrates how these issues can be addressed with therapeutic approaches to rescue folding, ameliorate downstream consequences of aberrant polymerization and/or maintain physiological function. Small-molecule strategies have successfully targeted structural features of the native conformer. Recent developments include the capability to follow solution behavior of α1-antitrypsin in the context of disease mutations and interactions with drug-like compounds. Moreover, preclinical studies in cells and organisms support the potential of manipulating cellular response repertoires to process misfolded and polymer states.

Update on alpha-1 antitrypsin deficiency: New therapies

“…However we now know the latter assumption was incorrect, and the former assumption is also a matter of debate [22]. An alternative linkage was suggested by the crystal structures of a dimer of antithrombin in which the molecules were linked by a β-hairpin of the reactive centre loop and strand 5A [25] (Fig.…”

“…Understanding the polymerogenic behaviour of the most clinically-significant variant is important as it has relevance for the readouts that may be used in screening for therapeutic agents [16,22]. Conversely, understanding the behaviour of rarer or milder variants in addition opens the way to precision medicine approaches, analogous to recent advances in cystic fibrosis [23,24].…”

Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin

“…Loss of functional AAT in the lung leads to emphysema and/or chronic obstructive pulmonary disease (COPD) (9). Thus, AATD is considered a ‘protein conformational disease’ (10, 11). Understanding and managing the balance between evolutionary diverse protein fold trajectories and the driving force of proteostasis system in managing folding with trafficking and function represents a largely untested mechanism for disease intervention through the development of proteostasis targeted therapeutics (12).…”

An integrative approach combining ion mobility mass spectrometry, X‐ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1‐antitrypsin upon ligand binding

“…The clinical need remains largely unmet: no specific treatment other than organ transplantation has proven robustly effective in stabilizing the associated liver or lung disease. 11 Its disease mechanisms, however, are among the best characterized of any human disease, and hence extensive efforts are underway to translate these scientific insights into novel therapeutic strategies. 11,12 The general process of a 1 -antitrypsin polymerization is driven by thermodynamic considerations.…”

“…11 Its disease mechanisms, however, are among the best characterized of any human disease, and hence extensive efforts are underway to translate these scientific insights into novel therapeutic strategies. 11,12 The general process of a 1 -antitrypsin polymerization is driven by thermodynamic considerations. It proceeds from a metastable native state, via an unstable monomeric intermediate state that is polymerogenic (M*), to a hyperstable polymer assembly.…”