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Int. J. Mol. Sci. 2017, 18(7), 1575;

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
Author to whom correspondence should be addressed.
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)
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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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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