Synthesis and Metabolism of Drugs by Means of Enzyme-Catalysed Reactions

The usefulness of enzyme catalysed-reactions is exemplified by recent results from research at Roche.Sequences of enzyme reactions, well organised in metabolic pathways of selected microorganisms, lead to secondary metabolites with innovative chemical structures. An example is the pancreas-lipase inhibitor lipstatin produced by Streptomyces toxytricini. Hydrogenation of lipstatin yields tetrahydrolipstatin, the active substance of the anti-obesity drug Xenical™. The biosynthetic pathway has been elucidated and an improved fermentation process for the production of lipstatin has been developed.Intermediates of the primary metabolism can be valuable building blocks for the chemical synthesis of drugs. Examples are quinic acid and shikimic acid, which are both suitable starting materials for the synthesis of the neuraminidase inhibitor GS 4104. Metabolic engineering of Escherichia coli with the goal to overproduce these two substances is briefly described.Microorganisms or enzymes derived thereof are used in drug synthesis to catalyse single, highly specific reaction steps (biotransformations). Three examples yielding chiral precursors of a protein-kinase inhibitor, a collagenase inhibitor, and an antifungal compound are discussed.Recombinant Escherichia coli strains expressing human drug-metabolising enzymes are suited to mimic drug metabolism and to produce intermediates of human drug metabolism. The desired hydroxylated drug derivatives could be obtained after incubation of drug substances with strains coexpressing one specific human cytochrome P450 isozyme together with human reductase

Cytomegalovirus and polyomavirus BK posttransplant

Virus replication and progression to disease in transplant patients is determined by patient-, graft- and virus-specific factors. This complex interaction is modulated by the net state of immunosuppression and its impact on virus-specific cellular immunity. Due to the increasing potency of immunosuppressive regimens, graft rejections have decreased, but susceptibility to infections has increased. Therefore, cytomegalovirus (CMV) remains the most important viral pathogen posttransplant despite availability of effective antiviral drugs and validated strategies for prophylactic, preemptive and therapeutic intervention. CMV replication can affect almost every organ system, with frequent recurrences and increasing rates of antiviral resistance. Together with indirect long-term effects, CMV significantly reduces graft and patient survival after solid organ and hematopoietic stem cell transplantation. The human polyomavirus called BK virus (BKV), on the other hand, only recently surfaced as pathogen with organ tropism largely limited to the reno-urinary tract, manifesting as polyomavirus-associated nephropathy in kidney transplant and hemorrhagic cystitis in hematopoetic stem cell transplant patients. No licensed anti-polyoma viral drugs are available, and treatment relies mainly on improving immune functions to regain control over BKV replication. In this review, we discuss diagnostic and therapeutic aspects of CMV and BKV replication and disease posttransplantatio