The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES
AbstractDespite 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
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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.
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. International Journal of Molecular Sciences. 2017; 18(7):1575.Chicago/Turabian Style
F. Nguyen, Anna; S. Schill, Megan; Jian, Mike; J. LiWang, Patricia. 2017. "The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES." Int. J. Mol. Sci. 18, no. 7: 1575.
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