Targeting Extracellular Cyclophilin A via an Albumin‐Binding Cyclosporine A Analogue

An albumin‐binding CsA analogue 4MCsA was achieved by attachment of a thiol‐reactive maleimide group at the side‐chain of P4 position of CsA derivative. 4MCsA was semi‐synthesized from CsA, and the cell‐impermeability of albumin‐4MCsA was detected by mass spectrometry and a competitive flow cytometry. 4MCsA exhibits inhibition of chemotaxis activity and inflammation by targeting extracellular CypA without immunosuppressive effect and cellular toxicity. These combined results suggested that 4MCsA can be restricted extracellularly through covalently binding to Cys34 of albumin with its maleimide group, and regulate the functions of cyclophilin A extracellularly. Extracellularly targeted: we developed an albumin‐binding CsA analogue, 4MCsA, modified by a thiol‐reactive maleimide group. 4MCsA readily covalently binds to albumin residue Cys34 with the maleimide group, and is restricted extracellularly. 4MCsA has similar binding affinity for CypA as that of CsA, yet is devoid of immunosuppressive capacity and cellular toxicity. 4MCsA exhibits potent inhibition of chemotaxis activity and inflammation by targeting extracellular CypA.