Inhibitors of Fusion between Viral and Cell Membranes as well as Compositions and Methods of Using Them

Fusion between the viral and target cell membranes is a key step for the infectivity of enveloped viruses. Viral fusion is driven by specialized proteins that undergo a series of conformational changes to bring the viral and host membranes together and promote formation of a fusion pore.

Peptides derived from either N-terminal or C-terminal regions of fusion proteins from enveloped viruses can interfere with the structural rearrangements required for fusion, therefore can inhibit viral infectivity. However, the antiviral activity of the peptides differs considerably among enveloped viruses. It has been possible to increase potency by attaching a cholesterol group to the peptide and by combining cholesterol-tagging with dimerization.

Cornell researchers studied methods to improve the efficacy of peptide inhibitors for viral entry and discovered that conjugating tocopherol (or a derivative thereof) is able to significantly improve the efficacy of peptide inhibitors. The researchers designed peptide inhibitors for different viruses and conjugated the peptide inhibitors with tocopherol. They tested these novel peptide inhibitors in different animal models, e.g., the SLAM x IFNARKO mouse model for Measles virus infection, hamsters for Nipah virus infection, mice for Ebola virus infection and and cotton rats for human Parainfluenza Virus type 3. Compared to cholesterol conjugated peptide inhibitors, tocopherol conjugated peptide inhibitors demonstrated significantly improved efficacy. The peptide inhibitors also demonstrated the ability to cross the blood brain barrier. The researchers also optimized the linker region and the pharmaceutical compositions for higher efficacy.

Potential Applications

Viral fusion inhibitors for the prevention and treatment of viral infections

Advantages

• Compared to cholesterol conjugated inhibitors, tocopherol conjugated peptide inhibitors for viral fusion have significantly improved efficacy
• Optimized linkers and pharmaceutical compositions for higher efficacy
• The inhibitors are able to inhibit either intracellular or extracellular fusion of enveloped viruses