Cost and toxicity problems associated with highly active antiretroviral therapy (HAART) in HIV/AIDS treatment could be alleviated by using designed multiple ligands (DMLs). Dual inhibitors of HIV reverse transcriptase (RT) and integrase (IN) were rationally designed by introducing a diketoacid (DKA) functionality into the tolerant C-5 site of RT inhibitor delavirdine. The resulting compounds all demonstrate good activity against both RT and IN in enzymatic assays and HIV in cell-based assay, whereas their C-7 regioisomers are all inactive in these assays. Balanced activities were observed with C-3 halogenated inhibitors.
Bibliographical noteFunding Information:
This research was supported by the Center for Drug Design at the University of Minnesota. We thank Dr. Eric Bennett for discussion, Dr. Christine Salomon for IN assay and Christine Dreis for RT assay. We also thank Roger Ptak at Southern Research Institute for cell-based assay, Dr. Robert Craigie of NIH for the integrase plasmid and Dr. William Shannon for consultation and discussion.
Copyright 2009 Elsevier B.V., All rights reserved.
- Dual inhibitors
- Reverse transcriptase