New types of anti-HIV agents identified by the NCI drug discovery program. Eleventh International Conference on Antiviral Research

Through a combination of cell-based screening and rational drug design efforts to target selected viral macromolecules, a wide variety of new classes of anti-HIV agents have been identified. These include inhibitors of HIV-1 transcription, inhibitors of virus fusion that act by affecting chemokine co-receptors on cell surfaces, as well as inhibitors of the HIV-1 nucleocapsid protein. Temacrazine was developed as a nanomolar inhibitor of HIV-1 transcription that selectively inhibits synthesis of HIV-1 RNA without interference with transcription of cellular genes or events associated with the Tat and Rev regulatory proteins. This compound inhibits acute, latent and chronic HIV-1 infections and demonstrates in vivo anti-HIV-1 activity. A distamycin analog, designated as NSC 651016, prevents HIV from fusing with host cells by targeting chemokine co-receptors. NSC 651016 blocked chemokine binding to CCR5, CCR3 and CXCR4, but not to CXCR2 or CCR2b, and the compound inhibited HIV-1 replication in an in vivo model. A variety of chemotypes have been identified as inhibitors of the nucleocapsid protein zinc finger motifs. Such compounds demonstrate virucidal activity and prevent the formation of infectious virus from infected cells. Three compounds have been found to selectively disrupt the nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins. No drug-resistant isolates have been detected to the nucleocapsid protein zinc finger inhibitors, and two such compounds are currently in clinical trials. These examples illustrate a few of the new types of anti-HIV agents identified by the National Cancer Institute.

See More