Background: We have recently demonstrated by using phage peptide libraries as well as mutagenesis studies that metalloporphyrins, by binding to a novel and distinct site of HIV-1 reverse transcriptase (HIV-1 RT), which includes the 398-407 sequence from the connection subdomain of p66 subunit, inhibit enzymatic activity. In order to further study the clinical potential of synthetic metalloporphyrin compounds in the management of HIV-1 infection, we tested the inhibitory effect of a series of synthetic, highly soluble iron (Fe)-metalloporphyrins on HIV-1 replication in cell cultures and have identified compounds that are highly effective as well as non-toxic for T cells.

Methods: CEM cells (5x10⁵-10⁶) were infected with 1 ng p24 antigen of the T-tropic HIV-1 strain NL4-3. Metalloporphyrins were then added at different concentrations (0.1-50 mM), and infected cells were transferred in 24-well ELISA plates, in RPMI-1640 medium supplemented with 10% FBS at 37°C. Cultures were maintained in media for 8 days. 0.5-mL aliquots were removed on day 4 and day 8 and samples were assayed in duplicate for the HIV-1 p24 antigen with the NEN HIV-1 p24 Antigen ELISA detection system. Metalloporphyrin cytotoxicity was analyzed by Trypan Blue exclusion test of cell viability.

Results: The soluble Fe-derivatives of Meso-tetra(4-carboxyphenyl)porphine and Meso-tetra(4-sulfonatophenyl)porphine are the most potent inhibitors of viral replication. Furthermore, Meso-tetra(4-sulfonatophenyl)porphine, represents a novel antiretroviral, with the most potent inhibitory effect on HIV-1 replication, in the micromolar range. In addition, cytotoxicity studies indicated that all of the compounds tested are nontoxic for CEM T-cells even as high as 100 mM.

Conclusions: Water-soluble Fe-metalloporphyrins represent novel HIV-1 antiretrovirals, which exert a potent inhibitory effect on HIV-1 replication and are nontoxic for T-cells. These compounds are excellent candidates for the development of a new class of anti-HIV-1 drugs for the management of AIDS, and the treatment of HIV-1 infection. Further investigation of the inhibitory effects of these water-soluble compounds on HIV-1 replication is required, in the process of developing a novel class of effective, safe and inexpensive anti-HIV-1 drugs.