The Effect of N-Terminal Cyclization on the Function of the HIV Entry Inhibitor 5P12-RANTES
| Autor: | Patricia J. LiWang, Anna F Nguyen, Mike Jian, Megan S Schill |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Chemokine Magnetic Resonance Spectroscopy Amino Acid Motifs Chemokine (C-C Motif) Ligand 5 lcsh:Chemistry HIV Fusion Inhibitors Chemokine (C-C Motif) Ligand 5 (CCL5) Receptor lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification Molecular Structure General Medicine CC 3. Good health Computer Science Applications Amino acid Infectious Diseases Biochemistry 5.1 Pharmaceuticals Chemokines CC HIV/AIDS Development of treatments and therapeutic interventions Chemokines 5P12-RANTES medicine.drug 030106 microbiology CHO Cells Biology Article Catalysis CCL5 Cell Line Inorganic Chemistry Inhibitory Concentration 50 Structure-Activity Relationship 03 medical and health sciences N-terminal cyclization Cricetulus HIV entry inhibition chemokine Genetics medicine Animals Humans Potency Physical and Theoretical Chemistry Molecular Biology Chemical Physics Organic Chemistry Virus Internalization Entry inhibitor Glutamine 030104 developmental biology chemistry lcsh:Biology (General) lcsh:QD1-999 Cyclization HIV-1 biology.protein Other Biological Sciences Other Chemical Sciences CC chemokine receptors |
| Zdroj: | International Journal of Molecular Sciences, Vol 18, Iss 7, p 1575 (2017) International Journal of Molecular Sciences; Volume 18; Issue 7; Pages: 1575 International Journal of Molecular Sciences International journal of molecular sciences, vol 18, iss 7 |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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