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Abstract

The invention describes complexes between VB.sub.12 analogues and either GCSF or EPO that retain both significant affinity for intrinsic factor (IF) in the VB.sub.12 portion of the complex and significant bioactivity of the GCSF or EPO portion of the complex. The invention also concerns a process for the synthesis of these complexes. This is achieved at least in part, by using a spacer compound, which is linked covalantly between the VB.sub.12 portion and the GCSF or EPO. The complexes preferably have the formula V--X--A--Y--Z wherein V is vitamin B.sub.12 or a vitamin B.sub.12 analogue, or derivative, bonded to X either through a carboxylate group pendant to the corrin nucleus of VB.sub.12 or through the central cobalt atom or to a functional group introduced onto the VB.sub.12 molecule, X is selected from: --NHNH--, --NH--, --O--, --S--, --SS--or --CH.sub.2 --, and A is an optionally substituted, saturated or unsaturated, branched or linear, C.sub.1-50 alkylene, cycloalkylene or aromatic group, optionally with one or more carbons within the linear chain being replaced with N, O or S, and wherein the optional substituents are selected from carbonyl, carboxy, hydroxy, amino and other groups, and Y is the covalent linkage between A and Z where Y is selected from --NHCO--, --CONH--, --CONHNHCO--, --N.dbd.N--, --N.dbd.CH--, --NHCH.sub.2 --, --NHN.dbd.CH--, --NHNHCH.sub.2 --, --SS--, --SCH.sub.2 --, --CH.sub.2 S--, --NHCRNH--, --COO--, --OCO--, and R is O, S or NH.sub.2, and Z is GCSF or EPO. The invention also describes reagents that can be used as probes for the detection of buried thiol groups of a protein or peptide, said reagent comprising a complex of either vitamin B.sub.12 (or an analogue thereof) or more generally of any instrumentally or visually detectable label, covalently linked to a diradical spacer, said spacer having a terminal reactive group capable of forming a disulphide bond with a free thiol in said protein or peptides.

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First Claim