New understanding of how HSV-1 attacks cells

April 09, 2016

The team, led by microbiology, immunology and molecular genetics associate professor Robert Geraghty, said that after the virus binds to the cell surface, two proteins are triggered to merge with the cell's lipid layer, while a third protein "penetrates" the merged lipid layer to provide virus access to the cell.

The findings advance existing understanding of how HSV-1 attacks cells. Geraghty's earlier work had identified how a protein, Nectin-1, that is important for skin adhesion, is targeted by an HSV-1 protein, called "gD," that affixes itself to Nectin-1.

Immediately after gD has affixed itself to the skin cell's Nectin-1, the two proteins begin blending with the cell surface's lipid layer. Geraghty said those proteins are referred to as "gH" and "gL." After those two act on the cell's surface, a fourth protein, "gB," actually fuses with the skin cell to permit the virus to invade.

Geraghty's team is now screening peptides that could block the action of gH, gL and gB, thereby preventing the occurrence of HSV-1 infections or reducing the severity of HSV-1 episodes in herpes sufferers.

The research also has implications for understanding how similar viruses attack the body. Among the related viruses are cytomegalovirus, Epstein-Barr, Kaposi's sarcoma, varicella-zoster (causes chicken pox and shingles), and several animal herpes viruses, including those that attack horses, pigs and cattle.

Geraghty's project is funded under a five-year grant from the National Institute of Allergy and Infectious Diseases. The project is scheduled to end next February. His findings have been published in Virology , the Journal of General Virology and the Proceedings of the National Academy of Sciences .

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The most recent research involving LCPs has yielded a new investigational anti-tumor drug called Tolecine??, a compound that also has antiviral and antibacterial applications. Created by Tsai, it has been shown to be even more effective than the current standard of care for herpes.

The team's second patent application involves a formulation that combines Tolecine?? and another LCP, Apatone?, which attacks cancer cells via multiple pathways to offer improved efficacy. Apatone? has been successfully tested in more than 30 human tumor cell lines at Summa and in a Phase I/IIa clinical trial, which demonstrated a delaying effect in the progression of end-stage cancer patients. In addition, the FDA granted Apatone? orphan-drug status for the treatment of metastatic, or locally advanced, inoperable bladder cancer in August 2007.

Unlike other chemotherapy drugs, TolecineTM and Apatone? have low toxicity and do not target dividing cells. Instead, they are activated by inflammation that occurs in and around tumor cells, sparing healthy cells. ???We want to kill cancer cells specifically without killing surrounding tissues,??? says Jamison.

Innovative, low-toxicity drugs such as Tolecine?? and Apatone? provide new hope in the battle against cancer and other diseases in the next few years. ???Research on LCPs provides a solid scientific foundation for generations of new drugs,??? says Miller. Adds Tsai: ???LCPs are an untapped frontier from which many new, exciting treatments are now emerging.

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