News – Page 49 – Drug Discovery Opinion

More Benefits of ACE Inhibition and Angiotensin Receptor Blockade

Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) were developed primarily to treat hypertension, but several recent studies have shown that they could have additional benefits.

captopril In one study, mice in which the gene for ACE had been deleted were found to have lower body weight and a lower proportion of body fat than their wild type litter mates. The decreased body fat in the ACE knock-out mice was independent of food intake and appeared to be due to increased metabolism of fatty acids in the liver, with an additional effect of increased glucose tolerance.

Another study found that use of either ACE inhibitors or Angiotensin Receptor Blockers (ARBs) significantly reduced basal cell carcinoma and squamous cell carcinoma in patients at high risk of these keratinocyte cancers.

High levels of Angiotensin II have also been linked to the pro-angiogenic protein, vascular endothelial growth factor (VEGF) in pancreatic ductal adenocarcinoma (PDA).

losartan An ARB significantly inhibited the Angiotensin II induced increase in VEGF in PDA cell lines and, in an earlier study, an ACE inhibitor was shown to have a similar effect. These studies suggest that ACE inhibitors and ARBs may represent potential novel and promising strategies for controlling angiogenesis, prevention of metastasis, and prolongation of survival in patients with primary or metastatic PDA.

Sex Difference in Response to SSRIs

A recent study suggests that women respond better than men to a commonly used antidepressant medicine, citalopram. The study was designed to compare a large sample of patients in both primary and speciality psychiatric care settings. Although the women had more severe disease at baseline, they responded better to citalopram treatment and experienced more remissions than did the men.

Citalopram belongs to the class of drugs known as selective serotonin reuptake inhibitors (SSRIs). Low serotonin levels are believed to contribute to both mild and severe cases of depression; SSRIs increase serotonin levels at the synapse by blocking reuptake into the presynaptic cell. Citalopram is a racemic mixture; the active S-enantiomer is known as escitalopram.

Although men also benefitted from treatment with citalopram, the authors suggest that the greater response in women may be attributable to sex-specific biological differences, particularly in serotonergic systems. Previous studies have shown that women have lower levels of the serotonin reuptake transporter than men as well as higher levels of the most common serotonin receptor and that there are important differences in the way that men and women react to reductions in serotonin function.

New Regimen for Breast Cancer?

A recent report suggests that treatment with a combination of two commonly used anti-cancer drugs, doxorubicin and zoledronic acid, may benefit women with breast cancer. Doxorubicin is an anthracycline antibiotic that is widely used in cancer chemotherapy. It is thought to work by intercalating DNA and preventing cell replication.

Zoledronic acid is a third generation bisphosphonate that is used to prevent fractures in cancer patients with bone metastases. The bone destruction associated with malignancy develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The bisphosphonate drugs act by inhibiting osteoclast function.

Zoledronic acid and other bisphosphonates are also used to treat osteoporosis – a single dose of zoledronic acid has been shown to increase bone mineral density for up to a year.

The new study looked at the effects of the two drugs given alone, sequentially , or in combination on the growth of established breast tumours in mice. Alone out of the treatment methods, doxorubicin followed 24 hours later by zoledronic acid almost completely abolished tumor growth in the absence of bone disease. Zoledronic acid has already been shown to reduce the risks of fractures in breast cancer patients with bone metastases and the new study provides hope that new dosing regimens may provide additional benefits.

Structure of Telomerase Revealed

Telomeres are repetitive sequences at the 3’-end of DNA which protect the end of the chromosome from destruction during cell division. During the process, the telomeres are themselves destroyed and this mechanism normally limits cells to a fixed number of divisions. Embryonic stem cells express an enzyme, telomerase, which replaces the telomeres and allows the cells to divide repeatedly. Telomerase remains active in some rapidly dividing adult cells, but is switched off almost completely in most other cells to prevent excessive proliferation. Cancer cells often regain telomerase activity and are able to replicate indefinitely. Telomerase activity has been observed in approximately 90% of human tumours and inhibition of this enzyme is seen as a potential treatment for many cancers.

The telomerase is a reverse transcriptase that carries its own RNA primer sequence and has some similarities to the retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. The first telomerase inhibitor to enter clinical trials for the treatment of cancer is GRN163L, a lipid-conjugated thiophosphoramidate. GRN163L is resistant to nuclease digestion in blood and tissues and has very high affinity and specificity for telomerase.

Small molecule inhibitors such as BIBR1532, which inhibits telomerase activity in vitro with an IC₅₀ in the low nanomolar range, have also been identified. The nucleoside analogue AZT, which is used to treat HIV by inhibiting the viral reverse transcriptase, weakly inhibits telomerase activity.
An advance online publication in the journal Nature describes a high resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT (Telomerase Reverse Transcriptase).

It is hoped that the new structure will help in the design of small molecule telomerase inhibitors. As well as de novo design, the similarity between TERT and HIV reverse transcriptase suggests that it may be possible to modify reverse transcriptase inhibitors to inhibit telomerase. Such compounds could potentially be used to treat a wide range of cancers.

Not Seeing Eye to Eye

Age-Related Macular Degeneration (AMD) is a condition in which the centre of the retina (the macula) gradually deteriorates, and the detailed vision needed for reading, driving and recognizing faces is lost. There are two types of AMD, a dry form and a wet form: the dry form is more common, but less severe, than the wet form. In the dry form, the cells don’t take in enough vital nutrients and fail to clear cellular by-products so that eventually photoreceptors are lost from the central part of the eye. The wet form is characterised by the growth of new blood vessels which can bleed and leak fluid, leading to scarring and more rapid loss of vision. There is currently no specific treatment for dry AMD, whilst treatment for the wet form involves laser treatment to seal the leaking blood vessels or injection of anti-vascular endothelial growth factor (anti-VEGF) drugs directly into the eye.

A report in the New England Journal of Medicine now warns that a new treatment being developed for the treatment of wet AMD may actually cause harm in patients with the dry form of the disease. The new treatment, which is currently undergoing clinical trials, uses interfering RNA (RNAi) technology to downregulate production of VEGF or VEGF receptors. The new study identifies a link between toll-like receptor 3 (TLR3), which helps the immune system to recognize viral infections, and dry AMD. A mutation associated with low activity of TLR3 appears to offer protection against dry AMD, possibly by suppressing death of retinal cells. The use of RNAi induces TLR3 activation, and so could worsen the prognosis in patients with dry AMD. The discovery also suggests that TLR3 inhibitors may offer a potential new treatment for the more common, dry, form of AMD.

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

Boc5 Metabolic 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

Quorum 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.
LED209
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.

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-417 A 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.

Rapamycin

A 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.