title: Therapeutic targeting of misfolding and conformational change in α1-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.
authors: Institute of Structural & Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, Malet Street, London, WC1E 7HX, UK.
authors: Mun Peak
authors: MP
authors: Nyon
authors: Bibek
authors: B
authors: Gooptu
mesh_terms: D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D054852:Small Molecule Libraries; D000515:alpha 1-Antitrypsin