Isoform-Specific Inhibition of Cyclophilins Daum, Sebastian; Schumann, Michael; Mathea, Sebastian ...
Biochemistry (Easton),
07/2009, Letnik:
48, Številka:
26
Journal Article
Recenzirano
Odprti dostop
Cyclophilins belong to the enzyme class of peptidyl prolyl cis−trans isomerases which catalyze the cis−trans isomerization of prolyl bonds in peptides and proteins in different folding states. ...Cyclophilins have been shown to be involved in a multitude of cellular functions like cell growth, proliferation, and motility. Among the 20 human cyclophilin isoenzymes, the two most abundant members of the cyclophilin family, CypA and CypB, exhibit specific cellular functions in several inflammatory diseases, cancer development, and HCV replication. A small-molecule inhibitor on the basis of aryl 1-indanylketones has now been shown to discriminate between CypA and CypB in vitro. CypA binding of this inhibitor has been characterized by fluorescence anisotropy- and isothermal titration calorimetry-based cyclosporin competition assays. Inhibition of CypA- but not CypB-mediated chemotaxis of mouse CD4+ T cells by the inhibitor provided biological proof of discrimination in vivo.
A good imitation: Aryl‐1‐indanyl ketones are found to be highly efficient, reversible, cell‐penetrating inhibitors of the human peptidyl prolyl cis/trans isomerase Pin1. Owing to their structure 1, ...they are assumed to mimic the transition state 2 of the enzymatically catalyzed rotation about the imidic peptide bond preceding a proline residue.
The novel 3H-spiro1-benzofuran-2-cyclopentan-3-one skeleton has been made accessible by different routes. One- and two-step protocols lead to tricyclic and tetracyclic benzofuranones 2 and 3, ...respectively. A four-step synthesis to spirocompound 4 is described. The novel spirocyclic benzofuranones display modest to no inhibition of the human peptidyl prolyl cis/trans isomerase Pin1.
Geschickt imitiert: Aryl‐1‐indanylketone erweisen sich als hocheffiziente, reversible und zellgängige Inhibitoren der humanen Peptidyl‐Prolyl‐cis/trans‐Isomerase Pin1. Aufgrund ihrer Struktur 1 wird ...angenommen, dass sie den Übergangszustand 2 der enzymatisch katalysierten Rotation um die imidische Peptidbindung vor dem Prolin nachahmen.
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