The modification of antiviral drugs identified as effective against HTLV-III/LAV/HIV in vitro by the screening efforts of NIAID or National Cooperative Drug Discovery Groups for the Treatment of AIDS (NCDDG-AIDS) may be required to allow the delivery of drugs to the central nervous system (CNS). Thus, the objective of this proposed project is to ensure that efforts will be made now to develop the expertise necessary to deliver drugs to the CNS. NIAID, in collaboration with the United States Army Research Development Command, has established a rapid, in vitro screening program to evaluate the effectiveness of potential HTLV- III/LAV/HIV drugs. NIAID will undertake the lead role this year, in collaboration with NCI, in organizing scientists into groups focused on the discovery of novel drugs for the treatment of AIDS (NCDDG-AIDS). Through these efforts and other independent efforts, drugs which will prevent the replication of retroviruses will be identified and developed by the AIDS Program. Drugs which prevent HTLV-III/LAV/HIV replication may cross the blood brain barrier and achieve therapeutic levels efficiently, poorly or not at all. Recent reports have shown the ability to make dihydropyridine derivatives of nucleosides by the attachment of a chemical carrier through an ester linkage. These modified drugs (termed prodrugs) are greatly enhanced in their ability to cross the blood brain barrier. The successful development of improved methods for delivery and targeting of effective agents to the CNS will be especially beneficial to halt the progression of the disease, the spread of the infection and control a reservoir of the virus. The purpose of this solicitation is two-fold: first, to modify known antiretroviral drugs to increase their ability to cross the blood brain barrier; second, to encourage the development of innovative approaches for targeting drugs to the central nervous system.
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