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The Peptide Blockade

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Scientists have used molecular engineering techniques and a follow-up cell-based assay to block HIV entry into cells. In their work, published in August in the Proceedings of the National Academy of Sciences, they took advantage of the fact that engineered peptides can stably interact with cell surface proteins to block HIV infection of cells. In the future, the technique could be used as an alternative to current therapies that rely on antibody-based drugs, says lead author Sam Gellman, a chemist at the University of Wisconsin, Madison.

For many viruses — including HIV, influenza, Ebola, and the severe acute respiratory syndrome virus — protein-protein interactions between viral and host proteins are important for the virus to be able enter the cell it infects. In this study, Gellman's team created a set of peptide-like molecules that were then used to successfully block HIV infection in human cells in an in vitro cell-based assay. The assay work was done by Gellman's collaborators, John Moore and Min Lu at the Weill Medical College of Cornell University.

"If you look at biological systems at a molecular level, it's clear that what nature tells us is you want big, folded molecules to do complicated tasks, not the small molecules that most organic chemists tend to work with," Gellman says. "For a number of years, we've been interested in trying to take inspiration from proteins to create new kinds of molecules, basically by using different kinds of building blocks, in our case β-amino acids instead of α-amino acids."

Their synthetic peptides, which they've named foldamers, make a modest tweak to the backbone of the amino acid that ends up having a large functional effect. Instead of one carbon at the heart of the molecule, which is called an α-amino acid and is the usual structure, they engineered the amino acid to have two carbons. These beta amino acids change the shape of the resulting peptide, which they then used to bind to a crucial HIV membrane fusion protein, gp41, locking it into place and preventing it from letting the virus enter the cell.

"So essentially there's the potential for a parallel universe of beautifully complex, folded molecules of either pure β-amino acids or mixtures of α- and β-amino acids," Gellman says.

In the past, attempts to prevent infection by interfering with host-cell protein-protein interactions have not had widespread success, he says. Because most drugs are small molecules, they're not very effective at disengaging interactions between macromolecules like proteins. Smaller peptides work better, but they're broken down faster by enzymes in the body and so need to be administered often and in large doses. Gellman's foldamers are useful in that the two-stage design approach he employed — first creating a β-peptide and then chemically "rigidifying" the backbone — created peptides that are more resistant to natural degradation.

In a cell-based assay using one T-cell-line-adapted strain and three primary isolates of HIV, the Cornell team showed that the peptides prevented infection of a TZM-bl cell line. Although it is not clear that the foldamers themselves could ever be used as anti-HIV drugs, Gellman says, their study proves that using modified peptides to disrupt protein-protein interactions is a new way to think about designing molecules for antiviral therapies and other biomedical applications.

He hopes that his method will both enlighten the field and be broadly applicable in the future. "Perhaps you could create things that would mimic the recognition surfaces displayed by proteins and then use those things, as we use them in this [paper] — to block biomedically important protein-protein interactions," Gellman says.

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