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Peptides represent a promising source of new medicines, but improved technologies are needed to facilitate discovery and optimization campaigns. In particular, longer peptides with multiple disulfide bridges are challenging to produce, and producing large numbers of structurally related variants is dissuasively costly and time-consuming. The principal cost and time drivers are the multiple column chromatography purification steps that are used during the multistep chemical synthesis procedure, which involves both ligation and oxidative refolding steps. In this study, we developed a method for multiplex parallel synthesis of complex peptide analogs in which the structurally variant region of the molecule is produced as a small peptide on a 384-well synthesizer with subsequent ligation to the longer, structurally invariant region and oxidative refolding carried out in-well without any column purification steps. To test the method, we used a panel of 96 analogs of the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 (69 residues, two disulfide bridges), which had been synthesized using standard approaches and characterized pharmacologically in an earlier study. Although, as expected, the multiplex method generated chemokine analogs of lower purity than those produced in the original study, it was nonetheless possible to closely match the pharmacological attributes (anti-HIV potency, capacity to elicit G protein signaling, and capacity to elicit intracellular receptor sequestration) of each chemokine analog to reference data from the earlier study. This rapid, low-cost approach has the potential to support discovery and optimization campaigns based on analogs of other chemokines as well as those of other complex peptide and small protein targets of a similar size., (© 2018 Paolini-Bertrand et al.)

Because of the level of attention it received due to its role as the principal HIV coreceptor, CCR5 has been described as a 'celebrity' chemokine receptor. Here we describe the development of CCR5 inhibitory strategies that have been developed for HIV therapy and which are now additionally being considered for use in HIV prevention and cure. The wealth of CCR5-related tools that have been developed during the intensive investigation of CCR5 as an HIV drug target can now be turned towards the study of CCR5 as a model chemokine receptor. We also summarize what is currently known about the cell biology and pharmacology of CCR5, providing an update on new areas of investigation that have emerged in recent research. Finally, we discuss the potential of CCR5 as a drug target for diseases other than HIV, discussing the evidence linking CCR5 and its natural chemokine ligands with inflammatory diseases, particularly neuroinflammation, and certain cancers. These pathologies may provide new uses for the strategies for CCR5 blockade originally developed to combat HIV/AIDS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Of the two million people estimated to be newly infected with human immunodeficiency virus (HIV) every year, 95% live in poorer regions of the world where effective HIV treatment is not universally available. Strategies to reduce the spread of HIV infection, which predominantly occurs via sexual contact, are urgently required. In the absence of an effective vaccine, a number of approaches to prevent HIV infection have been developed. These include using potent anti-HIV drugs prophylactically, either through systemic administration or topical application to the mucosal tissues that HIV initially encounters during sexual transmission. Genetic deficiency of the chemokine receptor CCR5 provides individuals with a remarkable degree of protection from HIV acquisition. This is because CCR5 is the major coreceptor used by HIV to infect new target cells. Since CCR5 deficiency does not appear to carry any health disadvantages, targeting the receptor is a promising strategy for both therapy and prevention of HIV. In this review we first describe the advantages and limitations of the currently available strategies for HIV prevention, then we focus on strategies targeting CCR5, covering the progress that has been made in developing different classes of CCR5 inhibitors for prophylaxis, and the perspectives for their future development as new weapons in the global fight against HIV/AIDS.