Structure-activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists.

A new series of 2-aminoquinolines has been identified as antagonists of the melanin concentrating hormone receptor (MCH-1R). Syntheses and structure-activity relationships are described leading to a compound having low nanomolar activity against the receptor and demonstrating functional antagonism. Studies also showed that some of the compounds were selective against a range of other G protein-coupled receptors.

Development of a DNA-MVA/HIVA vaccine for Kenya.

Without going into the details of the devastation that human immunodeficiency virus (HIV) infection causes especially in the developing world, the best hope for changing the course of this epidemic is development of a safe, effective, accessible prophylactic HIV vaccine. While the inaccessibility of potentially neutralising epitopes on primary HIV isolates has hampered the development of envelope-based vaccines, there is a number of new potent technologies capable of inducing high levels of circulating virus-specific CD8(+) cytotoxic T lymphocytes (CTL). Our original finding that a successive immunisation with DNA and modified vaccinia virus Ankara (MVA) vaccines expressing a common immunogen is a potent way of inducing CD8(+) CTL, which has been since reinforced by us and others, prompted us to test this approach in humans. With the view of proceeding into a high-risk cohort in Kenya for the efficacy trial, we designed the immunogen, termed HIVA, to match the HIV strain responsible locally for over 70% infections. It consists of a consensus clade A gag p24/p17 and a string of clade A-derived CTL epitopes. Pre-clinical studies demonstrated high immunogenicities of both the pTHr.HIVA and MVA.HIVA vaccines. In mice, these induced strong T cells-mediated immune responses which lasted at least 155 days. In rhesus macaques, the prime-boost immunisation elicited T cell responses specific for multiple HIV-derived epitopes. Phase I trials in healthy low-risk volunteers have commenced in Oxford and Nairobi, and the preliminary immunogenicity analysis from the Oxford site indicated that both vaccine components alone induced T cell responses in a majority of volunteers. These results have boosted expectations for the prime-boost vaccinations.