CsAs biological activity

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The molecular basis of CsA s biological activity is the formation of a complex with the immunophilin cyclophilin A (CyPA) in such a way that the CsA-CyPA complex can associate with calcineurin (CN), which is a Ca2+/calmodulin-dependent Ser/Thr phosphatase. As a result, dephosphorylation of a nuclear factor of activated T-cells (NFAT) is inhibited. 

The elegant process, developed by Merck chemists [20], involved a catalytic amount of aromatic aldehyde. This facilitates racemization of the wrong enantiomer (3f )-6, in solution at ambient temperature, via an aldimine intermediate, which possesses a significantly more acidic C(3)-H (pA a 12) than the parent amine (p a 20). Due to the significantly lower solubility of its (-i-)-camphor-lO-sulphonic acid (CSA) salt, the desired enantiomer, (3S)-6, continuously crystallizes from the system in equilibrium. This efficient one-pot resolution-racemization process has been used on a multi-kilo scale, affording (3S)-6 for production of various biologically active compounds. 

Isolation of the immunophilin cDNAs has rendered possible the production and the structure-function study of these proteins by site-directed mutagenesis. In addition, yeast strains have been constructed where the endogenous ligands for CsA and FK506 have been replaced with their human counterparts. Such strains provide convenient assay systems for the stracture-activity studies of putative immunosuppressants (Koltin et al, 1991). The advances in immunosuppression are yet another salient example of the contributions of molecular biology to drug design and development. 

TCR refers to a repair pathway that preferentially and rapidly repairs lesions on the transcribed strand of active genes (less than 1% of human DNA) [47,48]. In TCR-NER the ability of a lesion to block RNA polymerases seems critical. The stalled polymerase recruits at least two TRC-specific factors CSA and CSB. The remainder of the TCR-NER pathway (i.e., unwinding, incision, excision, DNA synthesis, and ligation) may be identical to the GGR-NER pathway. The breast and ovarian cancer susceptibility gene BRCAl is involved in TCR [49,50] however, the exact biological function of the protein remains uncertain (for review see [51]). 

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