Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.15978-15983
• Main Authors: Zasloff, Michael, Adams, A. Paige, Beckerman, Bernard, Campbell, Ann, Han, Ziying, Luijten, Erik, Meza, Isaura, Julander, Justin, Mishra, Abhijit, Qu, Wei, Taylor, John M, Weaver, Scott C, Wong, Gerard C. L
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; antiviral properties; Antivirals; Biological Sciences; Cell Line; Cell Membrane - chemistry; Cell Membrane - drug effects; Cell membranes; Cells, Cultured; Cholestanols - chemistry; Cholestanols - pharmacology; Cricetinae; Deoxyribonucleic acid; DNA; Endothelial cells; Female; Fish; Hepatitis B virus - drug effects; Hepatitis B virus - growth & development; Hepatitis Delta Virus - drug effects; Hepatitis Delta Virus - growth & development; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - virology; Humans; Infections; Lipids; Liver; Male; Marine; Mesocricetus; Mice; Mice, Inbred BALB C; Molecular Structure; Muromegalovirus - drug effects; Muromegalovirus - growth & development; neutralization; P branes; pathogens; Petromyzon marinus; Petromyzontidae; rac1 GTP-Binding Protein - chemistry; Scattering, Small Angle; sharks; Squalus acanthias; Virus Diseases - drug therapy; Virus Diseases - virology; virus replication; Virus Replication - drug effects; Viruses; X-Ray Diffraction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1108558108

Antiviral compounds that increase the resistance of host tissues represent an attractive class of therapeutic. Here, we show that squalamine, a compound previously isolated from the tissues of the dogfish shark (Squalus acanthias) and the sea lamprey (Petromyzon marinus), exhibits broad-spectrum antiviral activity against human pathogens, which were studied in vitro as well as in vivo. Both RNA- and DNA-enveloped viruses are shown to be susceptible. The proposed mechanism involves the capacity of squalamine, a cationic amphipathic sterol, to neutralize the negative electrostatic surface charge of intracellular membranes in a way that renders the cell less effective in supporting viral replication. Because squalamine can be readily synthesized and has a known safety profile in man, we believe its potential as a broad-spectrum human antiviral agent should be explored.