Cholesterol conjugation potentiates the antiviral activity of an HIV immunoadhesin
| Autor: | Urbanowicz, Richard A., Lacek, Krzysztof, Lahm, Armin, Bienkowska-Szewczyk, Krystyna, Ball, Jonathan K., Nicosia, Alfredo, Cortese, Riccardo, Pessi, Antonello |
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| Přispěvatelé: | Urbanowicz, Richard A., Lacek, Krzysztof, Lahm, Armin, Bienkowska-Szewczyk, Krystyna, Ball, Jonathan K., Nicosia, Alfredo, Cortese, Riccardo, Pessi, Antonello |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Antiviral Agent
Pharmacology antibody engineering fusion inhibitor peptide antiviral Drug Discovery3003 Pharmaceutical Science Organic Chemistry Virus Internalization emerging viru Biochemistry lipid raft enveloped viru human immunodeficiency virus (HIV) Cholesterol HEK293 Cell Structural Biology Drug Design Peptide HIV-1 cholesterol conjugation Molecular Medicine viral entry HIV Infection Molecular Biology Human |
| Popis: | Immunoadhesins are engineered proteins combining the constant domain (Fc) of an antibody with a ligand-binding (adhesion) domain. They have significant potential as therapeutic agents, because they maintain the favourable pharmacokinetics of antibodies with an expanded repertoire of ligand-binding domains: proteins, peptides, or small molecules. We have recently reported that the addition of a cholesterol group to two HIV antibodies can dramatically improve their antiviral potency. Cholesterol, which can be conjugated at various positions in the antibody, including the constant (Fc) domain, endows the conjugate with affinity for the membrane lipid rafts, thus increasing its concentration at the site where viral entry occurs. Here, we extend this strategy to an HIV immunoadhesin, combining a cholesterol-conjugated Fc domain with the peptide fusion inhibitor C41. The immunoadhesin C41-Fc-chol displayed high affinity for Human Embryonic Kidney (HEK) 293 cells, and when tested on a panel of HIV-1 strains, it was considerably more potent than the unconjugated C41-Fc construct. Potentiation of antiviral activity was comparable to what was previously observed for the cholesterol-conjugated HIV antibodies. Given the key role of cholesterol in lipid raft formation and viral fusion, we expect that the same strategy should be broadly applicable to enveloped viruses, for many of which it is already known the sequence of a peptide fusion inhibitor similar to C41. Moreover, the sequence of heptad repeat-derived fusion inhibitors can often be predicted from genomic information alone, opening a path to immunoadhesins against emerging viruses. |
| Databáze: | OpenAIRE |
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