Deaminase, therapeutic enzyme

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

The principal drawback to treatment with vidarabine is the ready deamination by adenosine deaminase, an enzyme widely present in human tissues. Improved therapy is being attempted by simultaneously giving an inhibitor of this enzyme such as /Aro-9-(2-hydroxynon-3-yl)adenine 4,17) which has a little anti-viral action of its own. A more powerful inhibitor of this enzyme, pentostatin (deoxy-coformycin) 4,18) is also under investigation (Agarwal, Spector and Parks, 1977). It remains to be seen whether increasing the survival of vidarabine in this way can improve its therapeutic index which seems to be less than that of acyclovir. 

The molecule 7-aminopyrazolopyrimidine is related to the DNA base adenine. It is the base attached to ribose in formycin A, which is believed to have potential therapeutic value. It is also shown in Figure 5. There is a paradox in this system. This molecule is deactivated by the enzyme adenosine deaminase (ADA). In solution the N7H tautomer predominates. This structure however inhibits ADA, and this tautomer of formycin A would not be deactivated by the enzyme. 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

A few examples are also available in which the lack of a specific enzyme in some cells in the human body has enabled the development of a therapeutic agent. For example, guanine deaminase is absent from the cells of certain cancers but is abundant in healthy tissue as a result 8-azaguanine can be used therapeutically. 

---