Fusion/entry inhibitors as therapies for HIV.

A combination of three or more antiretroviral drugs, commonly termed 'highly active antiretroviral therapy' (HAART), has become the standard-of-care treatment for HIV-related disease in the developed world. Since its initiation in the mid 1990s, HAART has led to substantial reductions in both mortality and morbidity. There are, however, significant problems associated with existing therapies including high pill burdens and serious side effects in many patients, as well as the emergence and transmission of drug-resistant HIV variants. There is, therefore, a need for new medicines to treat HIV infections, both from the existing drug classes and, perhaps more importantly, a need for medicines that act against the virus in entirely new ways. In recent years, much has been learned about how HIV enters its target cells and this work has led to the identification of compounds that potently inhibit the individual steps of viral entry. The status of current research focussed on preventing HIV entry is described below.

The inhibitory activity of a peptide derivative against the growth of simian immunodeficiency virus in C8166 cells.

The peptide derivative Ro 31-8959 is a potent and selective inhibitor of the aspartic proteinases encoded by HIV-1 and HIV-2 and it arrests the growth of both viruses in cell culture. We have demonstrated similar effects against the simian immunodeficiency virus SIVmac251 in the human T-cell line, C8166 (ED50 = 6nM) with a therapeutic index of 4,500. The antiviral activity of Ro 31-8959 was 250 and 22 times greater than that of ddI and ddC, respectively. The mode of action was confirmed by accumulation of the polyprotein p55 with concomitant reduction of the cleavage product, p27, and by the production of immature virions.

The design of a novel class of potassium channel activating drugs, 2-(2,2-dimethylbenzopyran-4-yl)-pyridine-1-oxides.

The features of cromakalim responsible for its potassium channel activating property were investigated. A hypothesis relating three-dimensional structure to binding to a putative receptor was developed and used successfully to design the potent and structurally novel agents, 2-(2,2-dimethylbenzopyran-4-yl)-pyridine-1-oxides.

Effect of two novel inhibitors of the human immunodeficiency virus protease on the maturation of the HIV gag and gag-pol polyproteins.

The ability of two novel synthetic compounds to inhibit the HIV protease-mediated processing of HIV-1 precursor polyproteins was investigated in an in vitro gag-protease mixed lysate assay system and in an assay using recombinant baculoviruses engineered to express the HIV-1 gag and pol genes in cultured insect cells. With the in vitro mixed lysate assay we have shown that both compounds at 1 microM can completely inhibit the HIV-1 and HIV-2 protease-mediated release of p24 from the HIV-1 gag precursor at pH 5.5 and pH 7.0. In the intracellular baculovirus system these compounds were shown to inhibit the protease-mediated maturation of gag and also the excision of the protease moiety from its precursor.

New potent inhibitors of angiotensin converting enzyme.

Using an earlier model of the favoured orientation of binding functions of angiotensin converting enzyme (ACE) inhibitors, it has been possible to postulate a new, 7,6-bicyclic system, based on hexahydropyridazine, which might be expected to have high potency. Some members of this system which have been synthesised have been shown to be very active ACE inhibitors, in vitro and in vivo.