A Potent Strategy to Inhibit HIV-1 by Binding Both gp120 and gp41

Ioannis Kagiampakis², Arbi Gharibi¹, Marie K. Mankowski^†, Beth A. Snyder^†, Roger G. Ptak^†, Kristabelle Alatas¹, and Patricia J. LiWang¹*

The development of an anti-HIV microbicide is critical in the fight against the spread of HIV. It is shown here that covalently linking compounds that bind gp120 with those that bind gp41 can inhibit HIV entry even more potently than individual inhibitors or non-covalent combinations. The most striking example involves griffithsin, a potent HIV inhibitor that binds to the surface of HIV gp120. While griffithsin inhibits HIV Env-mediated fusion in a CCR5-tropic cell-cell fusion assay with an IC₅₀ of 1.31 ± 0.87 nM, and the gp41 binding peptide C37 shows an IC₅₀ of 18.2 ± 7.6 nM, the covalently linked combination of griffithsin with C37 (Griff37) exhibited an IC₅₀ of 0.15 ± 0.05 nM, 8.7-fold greater than griffithsin alone. Similarly, in CXCR4-tropic cell-cell fusion assays, Griff37 is 5.2-fold better than griffithsin alone. In viral assays, both griffithsin and Griff37 inhibit HIV replication at mid-picomolar levels, but the linked compound Griff37 is several-fold more potent than griffithsin alone against both CCR5- and CXCR4-tropic virus strains. Another example of this strategy includes the covalently linked combination of peptide C37 with a variant of the gp120-binding peptide CD4M33 (26). Also, NMR spectra for several of these compounds are shown, including, to our knowledge, the first published NMR spectrum for griffithsin.

Accepted by Antimicrobial Agents and Chemotherapy