Belgian scientists have designed a class of small molecules that inhibit HIV replication by blocking the virus’s ability to hijack the DNA of host cells (Nat. Chem. Biol., DOI: 10.1038/nchembio.370). The host cellular protein LEDGF/p75 is critical to HIV’s replication. This protein tethers the viral integrase enzyme to a cell’s chromosomes as HIV invades a host cell. Zeger Debyser of Catholic University of Leuven and coworkers developed a series of 2-(quinolin-3-yl)acetic acid derivatives, which they call LEDGINs, that suppress HIV by blocking the interaction between the host cell’s LEDGF/p75 and HIV integrase. Most antivirals aim to inhibit HIV enzyme activity or enzyme-substrate interactions, but LEDGINS, which haven’t shown any significant cellular toxicity, disrupt protein-protein interactions. “I think this is a decent start in the direction of a novel antiviral from a group that has already done a lot of important work in this area,” comments John M. Coffin of the National Cancer Institute’s HIV Drug Resistance Program.