O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor

Xiaoyang Guan, Patrick K. Chaffey, Huan Chen, Wei Feng, Xiuli Wei, Liu Meng Yang, Yuan Ruan, Xinfeng Wang, Yaohao Li, Kimberly B. Barosh, Amy H. Tran, Jaimie Zhu, Wei Liang, Yong Tang Zheng, Xu Wang, Zhongping Tan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Many human proteins have the potential to be developed as therapeutic agents. However, side effects caused by direct administration of natural proteins have significantly slowed expansion of protein therapeutics into the clinic. Post-translational modifications (PTMs) can improve protein properties, but because of significant knowledge gaps, we are considerably limited in our ability to apply PTMs to generate better protein therapeutics. Here, we seek to fill the gaps by studying the PTMs of a small representative chemotactic cytokine, RANTES. RANTES can inhibit HIV-1 infection by competing with it for binding to receptor CCR5 and stimulating CCR5 endocytosis. Unfortunately, RANTES can induce strong signaling, leading to severe inflammatory side effects. We apply a chemical biology approach to explore the potential of post-translationally modified RANTES as safe inhibitors of HIV-1 infection. We synthesized and systematically tested a library of RANTES isoforms for their ability to inhibit inflammatory signaling and prevent HIV-1 infection of primary human cells. Through this research, we revealed that most of the glycosylated variants have decreased inflammation-associated properties and identified one particular glyco variant, a truncated RANTES containing a Galβ1-3GalNAc disaccharide α-linked to Ser4, which stands out as having the best overall properties: relatively high HIV-1 inhibition potency but also weak inflammatory properties. Moreover, our results provided a structural basis for the observed changes in the properties of RANTES. Taken together, this work highlights the potential importance of glycosylation as an alternative strategy for developing CCR5 inhibitors to treat HIV-1 infection and, more generally, for reducing or eliminating unwanted properties of therapeutic proteins.

Original languageEnglish (US)
Pages (from-to)136-148
Number of pages13
JournalBiochemistry
Volume57
Issue number1
DOIs
StatePublished - Jan 9 2018

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Chemokine CCL5
Viruses
HIV-1
HIV Infections
Post Translational Protein Processing
Proteins
CCR5 Receptors
Glycosylation
Disaccharides
Therapeutics
Endocytosis
Chemokines
Protein Isoforms
Cells
Inflammation
Research

ASJC Scopus subject areas

  • Biochemistry

Cite this

Guan, X., Chaffey, P. K., Chen, H., Feng, W., Wei, X., Yang, L. M., ... Tan, Z. (2018). O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor. Biochemistry, 57(1), 136-148. https://doi.org/10.1021/acs.biochem.7b00875

O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor. / Guan, Xiaoyang; Chaffey, Patrick K.; Chen, Huan; Feng, Wei; Wei, Xiuli; Yang, Liu Meng; Ruan, Yuan; Wang, Xinfeng; Li, Yaohao; Barosh, Kimberly B.; Tran, Amy H.; Zhu, Jaimie; Liang, Wei; Zheng, Yong Tang; Wang, Xu; Tan, Zhongping.

In: Biochemistry, Vol. 57, No. 1, 09.01.2018, p. 136-148.

Research output: Contribution to journalArticle

Guan, X, Chaffey, PK, Chen, H, Feng, W, Wei, X, Yang, LM, Ruan, Y, Wang, X, Li, Y, Barosh, KB, Tran, AH, Zhu, J, Liang, W, Zheng, YT, Wang, X & Tan, Z 2018, 'O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor', Biochemistry, vol. 57, no. 1, pp. 136-148. https://doi.org/10.1021/acs.biochem.7b00875
Guan, Xiaoyang ; Chaffey, Patrick K. ; Chen, Huan ; Feng, Wei ; Wei, Xiuli ; Yang, Liu Meng ; Ruan, Yuan ; Wang, Xinfeng ; Li, Yaohao ; Barosh, Kimberly B. ; Tran, Amy H. ; Zhu, Jaimie ; Liang, Wei ; Zheng, Yong Tang ; Wang, Xu ; Tan, Zhongping. / O-GalNAcylation of RANTES Improves Its Properties as a Human Immunodeficiency Virus Type 1 Entry Inhibitor. In: Biochemistry. 2018 ; Vol. 57, No. 1. pp. 136-148.
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