%0 Journal Article %1 Napier2005Maraviroc %A Napier, Carolyn %A Sale, Harriet %A Mosley, Michael %A Rickett, Graham %A Dorr, Pat %A Mansfield, Roy %A Holbrook, Mark %D 2005 %J Biochemical Pharmacology %K drug drug-discovery drug-kinetics maraviroc %N 1–2 %P 163 - 172 %R https://doi.org/10.1016/j.bcp.2005.10.024 %T Molecular cloning and radioligand binding characterization of the chemokine receptor \CCR5\ from rhesus macaque and human %U http://www.sciencedirect.com/science/article/pii/S0006295205006787 %V 71 %X The aim of this study was to determine if macaque represents a suitable species for the pre-clinical evaluation of novel \CCR5\ antagonists, such as maraviroc (UK-427,857). To do this we cloned and expressed \CCR5\ from rhesus macaque and compared the binding properties of 125I-MIP-1β and 3H-maraviroc with human recombinant CCR5. 125I-MIP-1β bound with similar high affinity to \CCR5\ from macaque (Kd = 0.24 ± 0.05 nM) and human (Kd = 0.23 ± 0.05 nM) and with similar kinetic properties. In competition binding studies the affinity of a range of human chemokines for macaque \CCR5\ was also similar to human CCR5. Maraviroc inhibited binding of 125I-MIP-1β to \CCR5\ from macaque and human with similar potency (IC50 = 17.50 ± 1.24 nM and 7.18 ± 0.93 nM, respectively) and antagonised MIP-1β induced intracellular calcium release mediated through \CCR5\ from macaque and human with similar potency (IC50 = 17.50 ± 3.30 nM and 12.07 ± 1.89, respectively). 3H-maraviroc bound with high affinity to \CCR5\ from macaque (Kd = 1.36 ± 0.07 nM) and human (Kd = 0.86 ± 0.08 nM), but was found to dissociate ∼10-fold more quickly from macaque CCR5. However, as with the human receptor, maraviroc was shown to be a high affinity, potent functional antagonist of macaque \CCR5\ thereby indicating that the macaque should be a suitable species in which to evaluate the pharmacology, safety and potential mechanism-related toxicology of novel \CCR5\ antagonists.

@article{Napier2005Maraviroc, abstract = {The aim of this study was to determine if macaque represents a suitable species for the pre-clinical evaluation of novel \{CCR5\} antagonists, such as maraviroc (UK-427,857). To do this we cloned and expressed \{CCR5\} from rhesus macaque and compared the binding properties of [125I]-MIP-1β and [3H]-maraviroc with human recombinant CCR5. [125I]-MIP-1β bound with similar high affinity to \{CCR5\} from macaque (Kd = 0.24 ± 0.05 nM) and human (Kd = 0.23 ± 0.05 nM) and with similar kinetic properties. In competition binding studies the affinity of a range of human chemokines for macaque \{CCR5\} was also similar to human CCR5. Maraviroc inhibited binding of [125I]-MIP-1β to \{CCR5\} from macaque and human with similar potency (IC50 = 17.50 ± 1.24 nM and 7.18 ± 0.93 nM, respectively) and antagonised MIP-1β induced intracellular calcium release mediated through \{CCR5\} from macaque and human with similar potency (IC50 = 17.50 ± 3.30 nM and 12.07 ± 1.89, respectively). [3H]-maraviroc bound with high affinity to \{CCR5\} from macaque (Kd = 1.36 ± 0.07 nM) and human (Kd = 0.86 ± 0.08 nM), but was found to dissociate ∼10-fold more quickly from macaque CCR5. However, as with the human receptor, maraviroc was shown to be a high affinity, potent functional antagonist of macaque \{CCR5\} thereby indicating that the macaque should be a suitable species in which to evaluate the pharmacology, safety and potential mechanism-related toxicology of novel \{CCR5\} antagonists. }, added-at = {2017-06-22T18:42:42.000+0200}, author = {Napier, Carolyn and Sale, Harriet and Mosley, Michael and Rickett, Graham and Dorr, Pat and Mansfield, Roy and Holbrook, Mark}, biburl = {https://www.bibsonomy.org/bibtex/21032da59b8174fb5a91fdf9ce7480b78/salotz}, doi = {https://doi.org/10.1016/j.bcp.2005.10.024}, interhash = {1840e91bdea12510f64a1f7f47c2e919}, intrahash = {1032da59b8174fb5a91fdf9ce7480b78}, issn = {0006-2952}, journal = {Biochemical Pharmacology }, keywords = {drug drug-discovery drug-kinetics maraviroc}, number = {1–2}, pages = {163 - 172}, timestamp = {2017-06-22T18:42:42.000+0200}, title = {Molecular cloning and radioligand binding characterization of the chemokine receptor \{CCR5\} from rhesus macaque and human }, url = {http://www.sciencedirect.com/science/article/pii/S0006295205006787}, volume = 71, year = 2005 }