Non-peptide GLP-1 Agonist Shows Efficacy in Mouse Model of Diabetes

Boc5Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease, diabetes and obesity. A 39-residue synthetic peptide, Exenatide, which is approved for the treatment of type 2 diabetes, acts by mimicking the action of endogenous glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion.

Researchers have now shown that chronic administration of a non-peptide molecule, Boc5, can induce weight loss and increase insulin sensitivity in a mouse model of diabetes and obesity by binding to the receptor for GLP-1. Boc5 is the only non-peptide molecule reported so far that behaves as a full GLP-1 mimetic in vitro and in vivo. Although Boc5 itself does not have the properties of a ‘drug-like’ molecule, it may represent a starting point for the discovery of orally bioavailable agents with the potential to treat metabolic disorders.

Inhibiting Bacterial Signalling Reduces Virulence

bacteriaQuorum sensing is used by bacteria to coordinate gene expression according to local population densities. The bacteria secrete signalling molecules and have receptors that can specifically recognize signalling molecules released by other bacteria of the same or different species. When the concentration of the signalling molecule reaches a certain concentration (i.e. many bacteria in the location), a response is triggered.

In 2006, researchers at UT Southwestern Medical Center described how blocking a newly discovered receptor in a strain of E. Coli could prevent infection. When contaminated food containing a virulent strain of E. Coli is eaten, the bacteria cause no damage until they encounter signalling molecules produced by native gut flora together with the human hormones, adrenaline and noradrenaline. These molecular signals prompt the virulent E.Coli bacteria to release enterotoxins which, in extreme cases, can be fatal.

In a recent report in the journal Science, Dr Sperandio’s group now describe the activity of a small molecule, LED209, which doesn’t inhibit bacterial growth but which markedly inhibits the virulence of several bacterial strains, both in vitro and in infected animals.
Many bacterial pathogens rely on signalling pathways using the same “adrenergic-type” receptor to promote the expression of virulence factors, so inhibition of this pathway may offer a strategy for the development of new broad-spectrum antimicrobial drugs. It is also possible that antagonists of this signalling pathway may not give rise to the widespread resistance seen with traditional antimicrobial agents.

New Brain Delivery Strategy for Parkinson’s Disease

The blood-brain barrier (BBB) fulfills an essential role by restricting the entry of potentially neurotoxic chemicals into brain tissue. The downside of this protective function is that entry of therapeutic molecules into the brain may also be severely restricted; delivering adequate amounts of drugs is one of the biggest challenges in treating many brain diseases.

L-Dopa, used to treat Parkinson’s Disease, is transported into the brain using a carrier system (LAT 1) which normally transports large neutral amino acids. L-Dopa is close enough in structure to one of the endogenous substrates, phenylalanine, to gain entry using this transporter, but the constraints in terms of size and shape on the transported molecule mean that opportunities for such carrier-mediated transport are very limited.
blood brain barrier
Now Armagen Technologies has announced funding by the Michael J. Fox Foundation for Parkinson’s Research to develop a receptor-mediated system to deliver a neurotrophin into the brain. Receptor-mediated transport mechanisms involve attaching the drug molecule to a protein recognized by cell surface receptors and triggering an energy-dependant transcytosis. In this case, the neurotrophin, which protects the part of the brain that degenerates in Parkinson’s Disease, is fused to a monoclonal antibody which is able to cross the blood brain barrier and so deliver the neurotrophin into the brain tissue.

Receptor-mediated transport mechanisms offer greater flexibility in terms of the size and shape of drug molecules that can be transported, and are likely to be more widely applicable than carrier-mediated systems.

PAI-1 inhibitors Help to Clear Amyloid Peptides

Amyloid peptide oligomers are believed to contribute to the pathology of Alzheimer’s Disease and much effort has gone into developing inhibitors of the β- and γ-secretases which are key to production of these peptides. An alternative approach to reducing amyloid peptide levels would be to increase their degradation. A number of proteases, including neprilysin, insulin-degrading enzyme and plasmin have been shown to degrade amyloid peptides.

PAZ-417A recent report now describes how increasing plasmin levels by inhibiting plasminogen activator inhibitor-1 (PAI-1) can lead to lowered brain amyloid levels. The PAI-1 inhibitor, PAZ-417, was found to lower brain and plasma amyloid levels and reverse cognitive deficits in mouse models of Alzheimer’s Disease.

PAZ-417 is currently undergoing Phase I clinical studies to investigate safety, tolerability and pharmacokinetics in young and elderly volunteers.

mTORC1 and MAPK Inhibitors for Treatment of Cancer

Rapamycin is a macrolide antibiotic used as an immunosuppressant to prevent organ rejection in transplant patients. Rapamycin and analogues have also been found to have anti-proliferative properties and their effects have been studied in a variety of cancers. Despite early promise, however, clinical tests have proved less successful than had been hoped.


PD0325901A report in the Journal of Clinical Investigation now suggests a reason for this lack of success. The anti-tumour effects of rapamycin are brought about by inhibition of the mTORC1 (mammalian target of rapamycin complex 1) pathway which is activated in many cancers, but the new study shows that this inhibition leads to activation of the mitogen-activated protein kinase(MAPK) cascade which stimulates the growth of cancer cells. The authors showed that the MAPK inhibitor, PD0325901, enhanced the effect of rapamycin or an analogue, RAD001 in cancer cell lines, and a xenograft mouse model of cancer.

The results suggest that patient stratification based on molecular pathways and combined use of these drug families, both of which are currently used as single agents in the clinic, will provide more effective treatments for cancer.