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

Chen, J and Huang, D and Chen, W and Guo, C and Wei, B and Wu, C and Peng, Z and Fan, J and Hou, Z and Fang, Y and Wang, Y and Kitazato, K and Yu, G and Zou, C and Qian, C and Xiong, S (2014) Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand. PLoS ONE, 9 (1).

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Abstract

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. © 2014 Chen et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chen, J
Huang, D
Chen, W
Guo, C
Wei, B
Wu, C
Peng, Z
Fan, J
Hou, Z
Fang, Y
Wang, Y
Kitazato, K
Yu, G
Zou, Cchz4@pitt.eduCHZ40000-0003-1355-4726
Qian, C
Xiong, Ssxiong@pitt.eduSXIONG
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHan, ZhaozhongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 27 January 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 1
DOI or Unique Handle: 10.1371/journal.pone.0086455
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Date Deposited: 19 Jun 2014 17:02
Last Modified: 01 Jul 2019 14:02
URI: http://d-scholarship.pitt.edu/id/eprint/21886

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