Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

High Throughput Screening Identifies Novel Lead Compounds with Activity against Larval, Juvenile and Adult Schistosoma mansoni.

An estimated 600 million people are affected by the helminth disease schistosomiasis caused by parasites of the genus Schistosoma. There is currently only one drug recommended for treating schistosomiasis, praziquantel (PZQ), which is effective against adult worms but not against the juvenile stage. In an attempt to identify improved drugs for treating the disease, we have carried out high throughput screening of a number of small molecule libraries with the aim of identifying lead compounds with balanced activity against all life stages of Schistosoma.

Staphylococcus aureus haem biosynthesis: characterisation of the enzymes involved in final steps of the pathway.

Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S.

Drug discovery for human African trypanosomiasis: identification of novel scaffolds by the newly developed HTS SYBR Green assay for Trypanosoma brucei.

Human African trypanosomiasis (HAT) is a vector-transmitted tropical disease caused by the protozoan parasite Trypanosoma brucei. High-throughput screening (HTS) of small-molecule libraries in whole-cell assays is one of the most frequently used approaches in drug discovery for infectious diseases. To aid in drug discovery efforts for HAT, the SYBR Green assay was developed for T.

Repositioning: the fast track to new anti-malarial medicines?

Background: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.

Methods: Molecules were tested initially against erythrocytic co-cultures of P.

Non-benzimidazole containing inhibitors of respiratory syncytial virus.

Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat.

Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs.

Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei.

An integrated transcriptomic and meta-analysis of hepatoma cells reveals factors that influence susceptibility to HCV infection.

Hepatitis C virus (HCV) is a global problem. To better understand HCV infection researchers employ in vitro HCV cell-culture (HCVcc) systems that use Huh-7 derived hepatoma cells that are particularly permissive to HCV infection. A variety of hyper-permissive cells have been subcloned for this purpose.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered.

Trypanosoma brucei glycogen synthase kinase-3, a target for anti-trypanosomal drug development: a public-private partnership to identify novel leads.

Background: Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), expresses two proteins with homology to human glycogen synthase kinase 3β (HsGSK-3) designated TbruGSK-3 short and TbruGSK-3 long. TbruGSK-3 short has previously been validated as a potential drug target and since this enzyme has also been pursued as a human drug target, a large number of inhibitors are available for screening against the parasite enzyme. A collaborative industrial/academic partnership facilitated by the World Health Organisation Tropical Diseases Research division (WHO TDR) was initiated to stimulate research aimed at identifying new drugs for treating HAT.

Small molecule drug discovery for Dengue and West Nile viruses: applying experience from hepatitis C virus.

There are currently no specific treatments for infection with Dengue virus (DENV) and West Nile Virus (WNV). Drug-discovery programs are underway for both viruses, but as yet no small molecules have advanced to clinical trials. Hepatitis C virus (HCV) is a related flavivirus that has been the focus of intense drug discovery efforts for the last two decades.

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.

HCV resistance to cyclosporin A does not correlate with a resistance of the NS5A-cyclophilin A interaction to cyclophilin inhibitors.

Background & Aims: The cyclophilin (Cyp) inhibitors - cyclosporine A (CsA), NIM811, Debio 025, and SCY 635 - block HCV replication both in vitro and in vivo, and represent a novel class of potent anti-HCV agents. We and others showed that HCV relies on cyclophilin A (CypA) to replicate. We demonstrated that the hydrophobic pocket of CypA, where Cyp inhibitors bind, and which controls the isomerase activity of CypA, is critical for HCV replication.

The use of AlphaLISA technology to detect interaction between hepatitis C virus-encoded NS5A and cyclophilin A.

Cyclosporine A (CsA) is an immunosuppressive molecule that also impedes replication of hepatitis C virus (HCV). CsA inhibits isomerase activity of cellular-encoded cyclophilin proteins, of which cyclophilin A (CypA) in particular is required for HCV replication. Evidence suggests that the HCV-encoded NS5A and NS5B proteins may govern dependence of the virus on CypA-mediated isomerase activity, although the molecular mechanisms involved are unclear.

Design and optimisation of potent gp120-CD4 inhibitors.

The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.

Discovery of a small molecule inhibitor through interference with the gp120-CD4 interaction.

A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.

The isomerase active site of cyclophilin A is critical for hepatitis C virus replication.

Cyclosporine A and nonimmunosuppressive cyclophilin (Cyp) inhibitors such as Debio 025, NIM811, and SCY-635 block hepatitis C virus (HCV) replication in vitro. This effect was recently confirmed in HCV-infected patients where Debio 025 treatment dramatically decreased HCV viral load, suggesting that Cyps inhibitors represent a novel class of anti-HCV agents. However, it remains unclear how these compounds control HCV replication.

Targeting the non-structural proteins of hepatitis C virus: beyond hepatitis C virus protease and polymerase.

Background: Chronic hepatitis C virus (HCV) infection is a main cause of cirrhosis of the liver and hepatocellular carcinoma. The standard of care is a combination of pegylated interferon with ribavirin, a regimen that has undesirable side effects and is frequently ineffective. Compounds targeting HCV protease and polymerase are in late-stage clinical trials and have been extensively reviewed elsewhere.

Comparison of rat and human responses to toll-like receptor 7 activation.

Toll-like receptors recognize invading microorganisms and activate innate immune responses. Their discovery has opened up a range of therapeutic possibilities, in particular for infectious diseases. Responses to TLR agonists have been largely studied in mice and little information exists in other species.

The future of toll-like receptor therapeutics.

Since the discovery of human TLRs, manipulating the activity of these receptors to modulate immune responses for therapeutic purposes has initiated intense activity in the pharmaceutical industry. The focus of these activities has been largely in the areas of infectious diseases, cancer, allergic diseases and vaccine adjuvants. Although initial clinical trials for infectious diseases and cancer showed early promise, subsequent longer-term trials have been disappointing and more research is required to find dosing regimes that balance efficacy with acceptable side-effect profiles.

Investigating Toll-like receptor agonists for potential to treat hepatitis C virus infection.

Toll-like receptors (TLRs) are key mediators of innate immunity, and their activation by microbial components leads to the production of cytokines and interferons. Recombinant alpha interferon has been used to treat several viral diseases and is the current standard of care for hepatitis C virus (HCV) infection. Recently, agonists of TLR7 and TLR9 have been shown to have clinical efficacy in HCV patients, and this is correlated with their ability to induce endogenous type I interferon production.

An inhibitor of the epidermal growth factor receptor function does not affect the ability of human papillomavirus 11 to form warts in the xenografted immunodeficient mouse model.

Epidermal growth factor receptor (EGFr) has been shown to be induced and activated in cells infected with HPV, suggesting that it may play a physiological role in viral replication or in the formation or maintenance of warts. To investigate this possibility, human foreskin tissue was infected with HPV11 and transplanted onto the renal capsule and the dermis of immunodeficient mice. The animals were treated orally or topically with the potent EGFr inhibitor CP-545130, with treatment starting either immediately following graft attachment, or following a 70 day period to allow development of warts.

Disruption of the gene encoding the ChiB1 chitinase of Aspergillus fumigatus and characterization of a recombinant gene product.

The gene encoding a major, inducible 45 kDa chitinase of Aspergillus fumigatus was cloned and analysis of the deduced amino acid sequence identified a chitinase of the fungal/bacterial class which was designated ChiB1. Recombinant ChiB1, expressed in Pichia pastoris, was shown to function by a retaining mechanism of action. That is, the beta-conformation of the chitin substrate linkage was preserved in the product in a manner typical of family 18 chitinases.

Novel small-molecule inhibitors of RNA polymerase III.

A genetic approach utilizing the yeast Saccharomyces cerevisiae was used to identify the target of antifungal compounds. This analysis led to the identification of small molecule inhibitors of RNA polymerase (Pol) III from Saccharomyces cerevisiae. Three lines of evidence show that UK-118005 inhibits cell growth by targeting RNA Pol III in yeast.

The impact of genomics on anti-infectives drug discovery and development.

Genomics and pharmacogenomics are signalling the start of a new era for the pharmaceutical industry. The successful integration of these technologies into the drug discovery process provides the promise of increased efficiency for pharmaceutical companies, with higher confidence in the targets they pursue and smarter design of clinical trials. There are benefits too for the consumer, with the possibility of customized drug treatments leading to improved efficacy and fewer side-effects.