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J Pept Sci. 2015 Sep;21(9):743-9. doi: 10.1002/psc.2802.

Cholesterol conjugation potentiates the antiviral activity of an HIV immunoadhesin.

Author information

1
School of Life Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.
2
Nottingham Digestive Diseases Centre Biomedical Research Unit, The University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.
3
CEINGE, Via Gaetano Salvatore 486, 80145, Napoli, Italy.
4
Laboratory of Virus Molecular Biology, University of Gdansk, 80-822, Gdansk, Poland.
5
PeptiPharma, Viale Città D'Europa 679, 00144, Roma, Italy.
6
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Napoli, Italy.
7
JV Bio, Via Gaetano Salvatore 486, 80145, Napoli, Italy.

Abstract

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.

KEYWORDS:

antibody engineering; cholesterol conjugation; emerging virus; enveloped virus; fusion inhibitor; human immunodeficiency virus (HIV); lipid raft; peptide antiviral; viral entry

PMID:
26292842
DOI:
10.1002/psc.2802
[Indexed for MEDLINE]

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