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Open AccessArticle

The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES

Molecular Cell Biology and the Health Sciences Research Institute, University of California Merced, 5200 North Lake Rd., Merced, CA 95343, USA
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Int. J. Mol. Sci. 2017, 18(7), 1575; https://doi.org/10.3390/ijms18071575
Received: 1 July 2017 / Revised: 12 July 2017 / Accepted: 14 July 2017 / Published: 20 July 2017
(This article belongs to the Special Issue Regulation of Chemokine-Receptor Interactions and Functions)
Despite effective treatment for those living with Human Immunodeficiency Virus (HIV), there are still two million new infections each year. Protein-based HIV entry inhibitors, being highly effective and specific, could be used to protect people from initial infection. One of the most promising of these for clinical use is 5P12-RANTES, a variant of the chemokine RANTES/CCL5. The N-terminal amino acid of 5P12-RANTES is glutamine (Gln; called Q0), a residue that is prone to spontaneous cyclization when at the N-terminus of a protein. It is not known how this cyclization affects the potency of the inhibitor or whether cyclization is necessary for the function of the protein, although the N-terminal region of RANTES has been shown to be critical for receptor interactions, with even small changes having a large effect. We have studied the kinetics of cyclization of 5P12-RANTES as well as N-terminal variations of the protein that either produce an identical cyclized terminus (Glu0) or that cannot similarly cyclize (Asn0, Phe0, Ile0, and Leu0). We find that the half life for N-terminal cyclization of Gln is roughly 20 h at pH 7.3 at 37 °C. However, our results show that cyclization is not necessary for the potency of this protein and that several replacement terminal amino acids produce nearly-equally potent HIV inhibitors while remaining CC chemokine receptor 5 (CCR5) antagonists. This work has ramifications for the production of active 5P12-RANTES for use in the clinic, while also opening the possibility of developing other inhibitors by varying the N-terminus of the protein. View Full-Text
Keywords: 5P12-RANTES; Chemokine (C-C Motif) Ligand 5 (CCL5); HIV entry inhibition; N-terminal cyclization; chemokine 5P12-RANTES; Chemokine (C-C Motif) Ligand 5 (CCL5); HIV entry inhibition; N-terminal cyclization; chemokine
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F. Nguyen, A.; S. Schill, M.; Jian, M.; J. LiWang, P. The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES. Int. J. Mol. Sci. 2017, 18, 1575.

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