Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand

Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction...

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Bibliographic Details
Published in:PloS one 2014-01, Vol.9 (1), p.e86455-e86455
Main Authors: Chen, Jia, Huang, Dane, Chen, Wei, Guo, Chaowan, Wei, Bo, Wu, Chongchao, Peng, Zhou, Fan, Jun, Hou, Zhibo, Fang, Yongsheng, Wang, Yifei, Kitazato, Kaio, Yu, Guoying, Zou, Chunbin, Qian, Chuiwen, Xiong, Sheng
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
AIDS
Analysis
Antiviral activity
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
Bacterial Proteins - pharmacology
Biological activity
Biology
Carrier Proteins - chemistry
Carrier Proteins - metabolism
Carrier Proteins - pharmacology
Cell fusion
Cell lines
Cyanovirin-N
Cytotoxicity
Dimerization
Drug Design
Engineering research
Glycan
Health aspects
HIV
HIV Infections - drug therapy
HIV-1 - drug effects
Human immunodeficiency virus
Humans
Immunogenicity
Immunology
Laboratories
Ligands
Lymphocytes T
Mannose
Medicine
Models, Molecular
Molecular docking
Molecular Docking Simulation
Monosaccharides
Mutation
N-glycans
N-Terminus
Oligosaccharides - metabolism
Polyethylene glycol
Polyethylene Glycols - metabolism
Polysaccharides
Protein Engineering - methods
Proteins
Toxicity
Viruses
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Summary:Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction of the reverse parallel CVN dimer with the oligosaccharide targets, among which Leu-1 was the most prominent hot spot residue. This finding provided a possible explanation for the lack of anti-HIV-1 activity observed with N-terminal PEGylated CVN. Therefore, linker-CVN (LCVN) was designed as a CVN derivative with a flexible and hydrophilic linker (Gly4Ser)3 at the N-terminus. The N-terminal α-amine of LCVN was PEGylated to create 10 K PEG-aldehyde (ALD)-LCVN. LCVN and 10 K PEG-ALD-LCVN retained the specificity and affinity of CVN for high mannose N-glycans. Moreover, LCVN exhibited significant anti-HIV-1 activity with attenuated cytotoxicity in the HaCaT keratinocyte cell line and MT-4 T lymphocyte cell lines. 10 K PEG-ALD-LCVN also efficiently inactivated HIV-1 with remarkably decreased cytotoxicity and pronounced cell-to-cell fusion inhibitory activity in vitro. The linker-extended CVN and the mono-PEGylated derivative were determined to be promising candidates for the development of an anti-HIV-1 agent. This derivatization approach provided a model for the PEGylation of biologic candidates without introducing point mutations.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0086455