Improving Drug Multiplicity

Nucleic-acid-based complexes that allow multiple copies of a bioactive chemical group to act together to potently inhibit biological targets have now been improved and found to be effective in animals. The work could lead to drugs for cancer and other diseases that use the power of multiplicity, or multivalency, to improve on conventional one-at-a-time, or univalent, medications.

Several research groups have recently added short peptide nucleic acids (PNAs), each bearing a bioactive ligand, to long single DNA strands to make DNA-PNA complexes that act as multivalent drugs, and they have tested the complexes in live cells.

Now, in Nature Communications (DOI: 10.1038/ncomms1629), synthetic organic chemist Daniel H. Appella of NIH’s National Institute of Diabetes & Digestive & Kidney Diseases and coworkers have created revised DNA-PNAs with multiple ligands per PNA. The complexes provide greater control than before over ligand number and density in DNA-PNAs, easing the way to determining which ones improve most on univalent drugs.

As ligands, they used analogs of Merck Serono’s univalent drug cilengitide, which is currently in Phase III trials for glioblastoma and Phase II trials for other cancers. Cilengitide helps prevent cancer metastasis by blocking integrin receptors on cancer cells. Appella and coworkers added different numbers of a cilengitide analog to PNAs and then used the ligand-PNAs to create DNA-PNAs having one to 45 total ligands.

In living melanoma cells and in mice given melanoma, multivalent DNA-PNAs with three ligands per PNA and 15 total ligands improved most on the antimelanoma activity of cilengitide, by about two orders of magnitude.

Oliver Seitz of Humboldt University, in Germany, a DNA-PNA pioneer, comments that Appella and coworkers “have pushed the field a significant step forward to applications. They are, to my best knowledge, the first to show that DNA-programmed multivalent display works in live animals. This is a major breakthrough that can move to the field of medicine.”