. This proposal is an outgrowth of an ongoing collaborative effort involving investigators at the University of Utah and the University of Tennessee under a joint contract entitled """"""""Targeting Drugs to the Central Nervous System for AIDS Therapy"""""""". The long-term aim of these proposed studies is to understand those processes governing the central nervous system (CNS) uptake of dideoxynucleosides and their derivatives so that more effective approaches for enhancing the CNS delivery of these agents can be developed to treat HIV infections in the brain. Dr. Anderson's group at the University of Utah will conduct in vitro and in vivo experiments and perform mathematical modelling studies of both existing dideoxynucleosides and new lead compounds to elucidate the contributions of both transport and enzyme mediated processes to the uptake and efflux kinetics. Dr. Baker's laboratory will synthesize new lead candidates, resynthesize some known compounds which may exhibit enhanced delivery to the brain, and provide novel inhibitors which may work in concert with chemical modification strategies to enhance CNS delivery.
The specific aims of this collaboration are: (1) Define the factors governing CNS entry (kin) and efflux (Kout) of dideoxynucleosides and explore the possible existence of an """"""""enzymatic blood-brain barrier"""""""" for dideoxynucleosides; (2) Further optimize the CNS delivery potential of adenosine deaminase (ADA) activated prodrugs of dideoxynucleosides (which have recently been shown to dramatically increase CNS uptake of 2',3'- dideoxyinosine ) by synthesizing a variety of novel 6-substituted dideoxypurines as potential ADA substrates and by exploring the inhibition of systemic ADA activity using inhibitors which do no cross the blood-brain barrier; (3) Combine the prodrug approach with inhibitors of efflux of the parent dideoxynucleosides from the CNS to obtain synergistic enhancement of CNS uptake modifying both Kin and Kout values; (4) Synthesize and evaluate novel dideoxypurine and/or dideoxypyrimidine nucleoside derivatives as substrates for xanthine oxidase and cytidine deaminase, both of which may be present at high levels in brain tissue or in brain capillary endothelial cells; (5) Develop structure-blood - brain barrier transport relationships for dideoxynucleosides.
