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

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, American Chemical Society.
    • Subject Terms:
      Protein Processing, Post-Translational*; Chemokine CCL5/*chemistry ; Chemokine CCL5/*pharmacology ; HIV Fusion Inhibitors/*chemistry ; HIV Fusion Inhibitors/*pharmacology ; HIV-1/*drug effects; Acylation ; Biopolymers ; Carbon-13 Magnetic Resonance Spectroscopy ; Chemokine CCL5/adverse effects ; Chemokine CCL5/metabolism ; Chemotaxis, Leukocyte/drug effects ; Glycosaminoglycans/metabolism ; Glycosylation ; HIV Fusion Inhibitors/adverse effects ; HIV Fusion Inhibitors/metabolism ; HIV Infections/drug therapy ; HIV-1/physiology ; Humans ; Proton Magnetic Resonance Spectroscopy ; Receptors, CCR5/metabolism ; THP-1 Cells
    • 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.
    • Accession Number:
      0 (Biopolymers)
      0 (CCR5 protein, human)
      0 (Chemokine CCL5)
      0 (Glycosaminoglycans)
      0 (HIV Fusion Inhibitors)
      0 (Receptors, CCR5)
    • Publication Date:
      Date Created: 20171205 Date Completed: 20180515 Latest Revision: 20180515
    • Publication Date:
      20240829
    • Accession Number:
      10.1021/acs.biochem.7b00875
    • Accession Number:
      29202246