Category: New Compounds and Treatments

Categories : Cardiovascular Disease New Compounds and TreatmentsTags :

Single Injection of New Anthypertensive Drug Could Reduce BP for Six Months

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A new drug which interferes with the production of angiotensin could help lower persistent hypertension for up to six months following a single injection, a study suggests. The results were published in the New England Journal of Medicine. If successful, the drug, called zilebesiran, would be more convenient for hypertension management than daily oral antihypertensive drugs.

More than half of patients with hypertension fail to take all of their prescribed medicine, leading to inconsistent blood pressure control. Better management of the condition could reduce the risk of stroke, heart attack and premature death, experts say.

Sustained drop

The international team, including experts from the University of Edinburgh’s Centre for Cardiovascular Science, ran the early stage clinical trials across four UK sites.

Patients who received zilebesiran experienced a substantial reduction in systolic blood pressure which lasted up to six months.

On average, systolic blood pressure lowered by over 10mmHg at a 200mg dose or more of the drug, and more than 20mmHg at the highest dose of 800mg. A drop of this size can take someone with hypertension to within a much safer range.

Blood pressure naturally goes up and down throughout the course of the day, making it difficult to treat – but the study found that the drop in blood pressure seen in patients who were treated with zilebesiran was consistent over 24 hours.

Novel approach

Developed by US-based company Alnylam, zilebesiran works by preventing the production of angiotensin, a hormone in the body that narrows blood vessels, leading to raised blood pressure. A number of existing antihypertensives also target angiotensin.

Zilebesiran uses a novel approach to interfere with the machinery in the liver that makes the protein angiotensinogen, the source of all forms of angiotensin.

Known as small interfering RNA (siRNA), zilebesiran turns off the gene responsible for producing angiotensinogen, preventing it from being made. 

The siRNA approach has already been used to develop treatments for a number of other conditions, with the ability to silence specific genes with high accuracy and effects lasting many months.

Safety data

107 patients with hypertension took part in the trial – 80 received a single injection of zilebesiran under the skin, while 32 received a placebo containing no active ingredients. Five patients who initially received the placebo were later moved to zilebesiran.

Experts caution that further studies involving a larger number of patients are needed to robustly investigate the safety of the drug and provide further insights into its potential to improve clinical outcomes in people with hypertension.

This is a potentially major development in hypertension. There has not been a new class of drug licensed for the treatment of high blood pressure in the last 17 years. This novel approach leads to a substantial reduction in blood pressure, both by day and night, that lasts for around six months after a single injection. This is attractive because it helps avoid the difficulty with adherence to treatment seen with current medicines. The next stage of clinical trials will focus on developing robust safety data, and broader evidence of efficacy, before zilebesiran can be licensed for use.

Professor David WebbChristison Chair of Therapeutics and Clinical Pharmacology at the University of Edinburgh, who led the Edinburgh study site

Source: University of Edinburgh

Categories : Neurodegenerative Diseases New Compounds and TreatmentsTags :

Third Alzheimer’s Drug is ‘Opening a Chapter in a New Era’

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With yet a third new Alzheimer’s drug, the monoclonal antibody donanemab, expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. But the drugs work best for those in the earliest stages of Alzheimer’s, and other therapies will be needed to help those with advanced disease, according to Gil Rabinovici, MD, director of the UCSF Alzheimer’s Disease Research Center.

This is likely “just the opening chapter in a new era of molecular therapies for Alzheimer’s disease and related neurodegenerative disorders,” Rabinovici wrote in an editorial that is being published along with the results of the latest drug, donanemab, in JAMA. Rabinovici was not involved in the trial.

Donanemab is a monoclonal antibody, like the two earlier Alzheimer’s drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer’s disease.

The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.

Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain.

While these results are encouraging, Rabinovici said an in-depth analysis still is needed to understand how these findings affect patient outcomes.

Limited benefit in advanced disease

Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Together with the drug’s potentially serious side effects, this should push experts to “aim higher in developing more impactful and safer treatments,” wrote Rabinovici, who is affiliated with the UCSF Memory and Aging Center, departments of Neurology, Radiology and Biomedical Imaging, as well as the Weill Institute for Neurosciences.

Donanemab should be restricted to patients with low-to-intermediate levels of tau, which indicates mild disease. Other trials are evaluating how well monoclonal antibodies work in the earliest phase of the disease before symptoms appear.

Like the two other new Alzheimer’s drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer’s. For that reason, Rabinovici said, genetic testing should be recommended prior to monoclonal antibody treatment.

While ARIA has generally been managed safely in clinical trials, Rabinovici urged caution as these drugs enter into real-world practice. He suggested limiting access to patients with normal pre-treatment MRIs, repeating MRIs at regular intervals and stopping or suspending treatment when ARIA occurs.

Lack of racial and ethnic diversity was a major limitation of the trial. Just 8.6% of the 1,251 U. S. participants were non-white. Rabinovici said this raises ethical concerns about the “generalisability of results to populations at highest risk,” noting studies that have shown higher rates of dementia in Black and Latino populations.

Given the anticipated high cost of donanemab and high patient demand, Rabinovici said it might make sense to limit the treatment duration to the time needed to clear amyloid plaques from the brain, which is the approach pioneered in the trial. He said this could “greatly enhance the feasibility of treatment for patients, clinicians, insurers and health systems.”

Source: University of California – San Francisco

Note: this article previously used an incorrectly attributed image. This has since been taken down and replaced.

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Peptides May Solve the Sticky Problem of Bacterial Biofilms

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This image shows an intricate colony of Pseudomonas aeruginosa. The bacteria have self-organised into a sticky, mat-like colony called a biofilm, which allows them to cooperate with each other, adapt to changes in their environment, and ensure their survival.
Credit: Scott Chimileski and Roberto Kolter, Harvard Medical School, Boston

Researchers have developed peptides that can help combat bacteria growing in biofilms, which occur in up to 80% of human infections. Their results, published in Nature Chemical Biology, may offer a way to tackle antimicrobial-resistant infections. 

Treating infections becomes significantly more challenging when biofilms are present, as they not only reduce the effectiveness of antibiotics but also give rise to several medical complications. These complications include infections following joint replacements, prosthetic devices, as well as contamination in catheters and other medical equipment. The lack of specific treatments makes the management and treatment of biofilms exceptionally difficult.

The team of researchers, led by Dr Clarissa Melo Czekster and Dr Christopher Harding from the School of Biology at St Andrews, in collaboration with researchers at University of Dundee, developed antimicrobial peptides that can target the harmful bacteria growing in biofilms.

The team determined how a key enzyme (PaAP) in biofilms work and developed a revolutionary new strategy to inhibit the protein. Their inhibitor is potent and targets cells from the human pathogen Pseudomonas aeruginosa in biofilms. P. aeruginosa, a WHO pathogen of concern, causes chronic infections in patients with cystic fibrosis and other conditions, which means a biofilm inhibitor is urgently needed.

Dr Czekster and the team are currently working in collaboration with the University of St Andrews Technology Transfer Centre and industry partner Locate Bio, a biomedicine spinout of the University of Nottingham, to commercialise the technology. The Locate Bio team are trialling the peptides to see how they work with the company’s Programmed Drug Release technology to develop new orthobiologic solutions and products. The Technology Transfer Centre has filed a UK priority patent application.

Dr Czekster said: “Our research reveals how designed inhibitors can target a key enzyme in bacterial virulence, offering molecular insights applicable to aminopeptidases in diverse organisms.

“This remarkable new research presents an innovative strategy to target bacterial biofilms and pave the way for better treatment of bacterial infection.”

Source: University of St. Andrews

Categories : Antibiotics New Compounds and TreatmentsTags :

Scientists Use Modified Peptides to Create New Class of Antibiotics

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New antibiotics are urgently needed to tackle resistant bacteria. Researchers at the University of Zurich and the company Spexis have now modified the chemical structure of naturally occurring peptides to develop antimicrobial molecules that bind to novel targets in the bacteria’s metabolism.

In a study recently published in Science Advances, chemist Oliver Zerbe, head of the NMR facilities at the University of Zurich now discusses the development of a highly effective class of antibiotics that fight Gram-negative bacteria in a novel way.

The WHO classifies this group of bacteria as extremely dangerous. The group, whose resistance is particularly high due to their double cell membrane, includes carbapenem-resistant enterobacteria, for example.

Natural peptide chemically optimised

The starting point for the researchers’ study was a naturally occurring peptide called thanatin, which insects use to fend off infections. Thanatin disrupts an important lipopolysaccharide transport bridge between the outer and inner membrane of Gram-negative bacteria, as revealed a few years ago in a study by now retired UZH professor John Robinson. As a result, these metabolites build up inside the cells, and the bacteria perish. However, thanatin isn’t suitable for use as an antibiotic drug, among other things due to its low effectiveness and because bacteria quickly become resistant to it.

The researchers therefore modified the chemical structure of thanatin to enhance the peptide’s characteristics. “To do this, structural analyses were essential,” says Zerbe. His team synthetically assembled the various components of the bacterial transport bridge and then used nuclear magnetic resonance (NMR) to visualize where and how thanatin binds to and disrupts the transport bridge. Using this information, researchers from Spexis AG planned the chemical modifications that were necessary to boost the peptide’s antibacterial effects. Further mutations were made to increase the molecule’s stability, among other things.

Effective, safe and immune to resistance

The synthetic peptides were then tested in mice with bacterial infections – and yielded outstanding results. “The novel antibiotics proved very effective, especially for treating lung infections,” says Zerbe. “They are also highly effective against carbapenem-resistant enterobacteria, where most other antibiotics fail.” In addition, the newly developed peptides aren’t toxic or harmful to the kidneys, and they also proved stable in the blood over a longer period – all of which are properties that are required for gaining approval as a drug. However, further preclinical studies are needed before the first tests in humans can begin.

When choosing the most promising peptides for their study, the researchers made sure that they would also be effective against bacteria that have already developed resistance to thanatin. “We’re confident this will significantly slow down the development of antibacterial resistance,” says Zerbe. “We now have the prospect of a new class of antibiotics becoming available that is also effective against resistant bacteria.”

Source: University of Zurich

Categories : Injury & Trauma New Compounds and TreatmentsTags :

New Compound Secreted by Bacteria Speeds up Healing

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Complicated, hard-to-heal wounds are a growing medical problem and there are currently only two drugs approved with proven efficacy. A new study published in eClinical Medicine shows that treatment with a specific type of modified lactic acid bacteria works well and has a positive effect on the healing of wounds.

Previously, the researchers had demonstrated accelerated wound healing after topical treatment using lactic acid bacteria (Limosilactobacillus reuteri) genetically modified to produce the chemokine CXCL12 (ILP100-Topical).

Now, in their first clinical study on humans, the researchers established safety and tolerability. Other objectives were to see clinical and biological effects on wound healing using traditionally accepted methods, as well as more exploratory and traceable measurements.

36 healthy volunteers were included in the study with a total of 240 induced wounds studied. The study’s design and methodology are described in more detail below.

The results show that treatment using ILP100-Topical was safe and well tolerated among all individuals and doses, and neither ILP100 nor CXCL12 could be detected in locations beyond the wounds. A significantly higher proportion of healed wounds (p=0.020) was seen on day 32 using multi-dose ILP100-Topical compared to saline and placebo (76% (73/96) and 59% (57/96) healed wounds respectively) when the results from the multi-dose-treated wounds were pooled. In addition, the time to first recorded healing was reduced by an average of 6 days, and by 10 days at the highest dose. The mechanism of action of ILP100-Topical was also confirmed when the treatment resulted in increased CXCL12-positive cells in the wounds, as well as increased blood flow around the wounds during the healing phase.

“Our study shows that bacteria modified to produce and deliver human protein for local effects can be used as drugs to accelerate the healing of wounds. This is the first time this has been shown in controlled human studies, and it can be expected that the effect is greater in patients with diseases that negatively affect wound healing,” explains Mia Phillipson, Professor at the Department of Medical Cell Biology at Uppsala University.

The favourable safety profile and the beneficial effects on wound healing observed here support further clinical development of ILP100-Topical for the treatment of complex and hard-to-heal wounds in patients, which is already under way.

Many immune-active proteins are inherently unstable and degrade quickly, so supplying them from lactic acid bacteria to the exact site of action is one way to develop them as drugs.

“The potential is really endless when you consider how important a role proteins play in various processes in the body, and how many diseases we currently do not have good enough treatments for. We have already produced another drug candidate to cure and reduce inflammation in the gut of cancer patients – ILP100-Oral – and in the future we will start a research project with another chemokine for the treatment of lung diseases,” concludes Phillipson.

Source: Uppsala University

Categories : New Compounds and Treatments Regenerative MedicineTags :

Researchers Identify New Compound that Could Stimulate Nerve Regeneration

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Research published in Nature has identified a new compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen in heart attack. The UCL-led study identified a chemical compound, named ‘1938’, that activates the PI3K signalling pathway, and is involved in cell growth.

Results from this early research, which was done in partnership with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca, showed the compound increased neuron growth in nerve cells, and in animal models, it reduced heart tissue damage after major trauma and regenerated lost motor function in a model of nerve injury.

Though further research is needed to translate these findings into the clinic, 1938 is one of just a few compounds in development that can promote nerve regeneration, for which there are currently no approved medicines.

Phosphoinositide 3-kinase (PI3K) is a type of enzyme that helps to control cell growth. It is active in various situations, such as initiating wound healing, but its functions can also be hijacked by cancer cells to allow them to proliferate. As a result, cancer drugs have been developed that inhibit PI3K to restrict tumour growth. But the clinical potential of activating the PI3K pathway remains underexplored.

Dr Roger Williams, a senior author of the study from the MRC Laboratory of Molecular Biology, said: “Kinases are ‘molecular machines’ that are key to controlling the activities of our cells, and they are targets for a wide range of drugs. Our aim was to find activators of one of these molecular machines, with the goal of making the machine work better. We found that we can directly activate a kinase with a small molecule to achieve therapeutic benefits in protecting hearts from injury and stimulating neural regeneration in animal studies.”

In this study, researchers from UCL and MRC LMB worked with researchers from AstraZeneca to screen thousands of molecules from its chemical compound library to create one that could activate the PI3K signalling pathway. They found that the compound named 1938 was able to activate PI3K reliably and its biological effect were assessed through experiments on cardiac tissue and nerve cells.

Researchers at UCL’s Hatter Cardiovascular Institute found that administering 1938 during the first 15 minutes of blood flow restoration following a heart attack provided substantial tissue protection in a preclinical model. Ordinarily, areas of dead tissue form when blood flow is restored that can lead to heart problems later in life.

When 1938 was added to lab-grown nerve cells, neuron growth was significantly increased. A rat model with a sciatic nerve injury was also tested, with delivery of 1938 to the injured nerve resulting in increased recovery in the hind leg muscle, indicative of nerve regeneration.

Senior author Professor James Phillips said: “There are currently no approved medicines to regenerate nerves, which can be damaged as a result of injury or disease, so there’s a huge unmet need. Our results show that there’s potential for drugs that activate PI3K to accelerate nerve regeneration and, crucially, localised delivery methods could avoid issues with off-target effects that have seen other compounds fail.”

Given the positive findings, the group is now working to develop new therapies for peripheral nerve damage, such as those sustained in serious hand and arm injuries. They are also exploring whether PI3K activators could be used to help treat damage in the central nervous system, for example due to spinal cord injury, stroke or neurodegenerative disease.

Source: University College London

Categories : Metabolic Disorders New Compounds and TreatmentsTags :

Experimental Drug may Prevent Diabetic Vision Loss

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Researchers at Wilmer Eye Institute, Johns Hopkins Medicine say they have evidence that an experimental drug may prevent or slow vision loss in people with diabetes. The results are from a study published in the Journal of Clinical Investigation, that used mouse models as well as human retinal organoids and eye cell lines.

The team focused on models of two common diabetic eye conditions: proliferative diabetic retinopathy and diabetic macular enema, both of which affect the retina, the light-sensing tissue at the back of the eye that also transmits vision signals to the brain. In proliferative diabetic retinopathy, new blood vessels overgrow on the retina’s surface, causing bleeding or retinal detachments and profound vision loss. In diabetic macular enema, blood vessels in the eye leak fluid, leading to swelling of the central retina, damaging the retinal cells responsible for central vision.

Results of the study show that a compound called 32-134D, previously shown to slow liver tumour growth in mice, prevented diabetic retinal vascular disease by decreasing levels of a protein called HIF, or hypoxia-inducible factor. Doses of 32-134D also appeared to be safer than another treatment that also targets HIF and is under investigation to treat diabetic eye disease.

Current treatment for both proliferative diabetic retinopathy and diabetic macular enema includes eye injections with anti-vascular endothelial growth factor (anti-VEGF) therapies. Anti-VEGF therapies can halt the growth and leakiness of blood vessels in the retina in patients with diabetes. However, these treatments aren’t effective for many patients, and may cause side effects with prolonged use, such as increased internal eye pressure or eye tissue damage.

Study author Akrit Sodhi, MD, PhD, says that in general, the idea of inhibiting HIF, a fundamental protein in the body, has raised concerns about toxicity to many tissues and organs. But when his team screened a library of HIF inhibitor drugs and conducted extensive testing, “We came to find that the drug examined in this study, 32-134D, was remarkably well tolerated in the eyes and effectively reduced HIF levels in diseased eyes,” says Sodhi.

HIF, a type of protein known as a transcription factor, has the ability to switch certain genes, including vascular endothelial growth factor (VEGF), on or off throughout the body. In the eye, elevated levels of HIF cause genes like VEGF to increase blood vessel production and leakiness in the retina, contributing to vision loss.

To test 32-134D, researchers dosed multiple types of human retinal cell lines associated with the expression of proteins that promote blood vessel production and leakiness. When they measured genes regulated by HIF in cells treated with 32-134D, they found that their expression had returned to near-normal levels, which is enough to halt new blood vessel creation and maintain blood vessels’ structural integrity.

Researchers also tested 32-134D in two different adult mouse models of diabetic eye disease. In both models, injections were administered into the eye. Five days post-injection, the researchers observed diminished levels of HIF, and also saw that the drug effectively inhibited the creation of new blood vessels or blocked vessel leakage, therefore slowing progression of the animals’ eye disease. Sodhi and his team said they also were surprised to find that 32-134D lasted in the retina at active levels for about 12 days following a single injection without causing retinal cell death or tissue wasting.

“This paper highlights how inhibiting HIF with 32-134D is not just a potentially effective therapeutic approach, but a safe one, too,” says Sodhi. “People facing diabetic eye disease and vision loss include our family members, friends, co-workers – this is a disease that impacts a large group of people. Having safer therapies is critical for this growing population of patients.”

Sodhi says that further studies in animal models are needed before moving to clinical trials.

Source: Johns Hopkins Medicine

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

FDA Approves First Drug Designed to Treat Indolent Systemic Mastocytosis

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Systemic mastocytosis (SM) is a rare haematologic disorder that can lead to a range of debilitating symptoms across multiple organ systems and a significant impact on patients’ quality of life, and now the first medicine has been approved to specifically treat the most common form of the disease. On Monday 22 May, the US Food and Drug Administration (FDA) approved AYVAKIT® (avapritinib) to treat indolent systemic mastocytosis (ISM) in adults.

ISM represents the vast majority of SM cases, and AYVAKIT is now available for adults with ISM at the recommended dose of 25mg once daily. AYVAKIT was designed to potently and selectively inhibit KIT D816V, the primary underlying driver of the disease. AYVAKIT has been FDA approved for the treatment of advanced SM since June 2021.

“After decades of caring for people with indolent systemic mastocytosis, I have seen firsthand its profound impact on patients’ underlying mast cell burden, symptoms, physical and mental health, and ability to work and participate in daily activities,” said investigator Cem Akin, MD, PhD, Professor of Medicine at the University of Michigan. “Despite the use of multiple supportive care treatments, a considerable number of patients with indolent systemic mastocytosis continue to experience a substantial disease burden. AYVAKIT advances the treatment of indolent systemic mastocytosis by targeting KIT D816V, the primary underlying cause of the disease, and establishes a new standard of care for a broad population of patients with this disorder. AYVAKIT delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those affected by the disease.”

The approval of AYVAKIT in ISM is based on data from the double-blind, placebo-controlled PIONEER trial – the largest study ever conducted for this disease – in which patients received AYVAKIT 25mg once daily plus best supportive care (AYVAKIT) or placebo plus best supportive care (placebo). AYVAKIT demonstrated significant improvements versus placebo in the primary and all key secondary endpoints, including overall symptoms and measures of mast cell burden.

AYVAKIT was well-tolerated with a favourable safety profile compared to placebo, and most adverse reactions were mild to moderate in severity. The most common adverse reactions for AYVAKIT (≥10%) were eye oedema, dizziness, peripheral oedema and flushing. Serious adverse reactions and discontinuations due to adverse reactions occurred in less than 1% of patients.

Detailed results from the PIONEER trial, including open-label extension study data showing the clinical benefits of AYVAKIT through 48 weeks of treatment, were presented in February 2023 at the American Academy of Allergy, Asthma & Immunology (AAAAI) Annual Meeting.

Source: Blueprint Medicines

Categories : Environmental Effects New Compounds and TreatmentsTags :

US to Trial Anti-radiation Pills That Could Protect Against Fallout from ‘Dirty Bombs’

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The US National Institutes of Health is funding a new clinical trial of an oral anti-radiation treatment. So-called dirty bombs are nuclear weapons that release a cloud of radioactive isotopes, and are thought to be an attractive option for terrorists because they are far easier to build than true nuclear explosives.

In such a situation, as well as a nuclear accident, the danger is not so much from direct radiation in the form of X-rays, gamma rays and alpha and beta particles, but from radioactive materials which are absorbed into the body via contaminated air, food or water. Certain radioisotopes from radioactive fallout are readily absorbed by the body, and cause damage to DNA and cellular structures. Current treatment contain chemicals that bind to these radioisotopes, preventing them from being taken up by the body and instead rapidly excreted.

The Food and Drug Administration has approved two products for removing internal radioactive contamination. These drugs, both based on diethylenetriamine pentaacetate (DTPA), are administered intravenously by a healthcare provider and can remove three radioactive elements: plutonium, americium, and curium. 

In contrast, HOPO 14-1 is an oral capsule, which would be easier than an intravenous drug to stockpile and to deploy and administer during an emergency. Preclinical research has shown that HOPO 14-1 can effectively remove many radioactive contaminants, including uranium and neptunium in addition to plutonium, americium and curium. These studies also have found that HOPO 14-1 is up to 100 times more effective than DTPA at binding and removing these radioactive elements.

The trial will seek 42 healthy volunteers aged 18 to 65, who will of course not be exposed to radioactive fallout. They will be assigned into seven groups of six. Each participant in the first group will receive a 100-milligram (mg) dose of HOPO 14-1. The subsequent groups will receive increasingly higher doses of the study drug up to 7500 mg in the final group, if lower doses are deemed safe. Participants will undergo intensive safety monitoring and will be followed for 14 days to measure the absorption, distribution and elimination of the study drug. Results are expected in 2024.

Source: National Institutes of Health

Categories : Mental Health New Compounds and TreatmentsTags :

Scientists Create Antidepressant Drug Candidates from Traditional African Plant Medicine

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Scientists have developed two new drug candidates for potentially treating addiction and depression, modelled on the pharmacology of a traditional African psychedelic plant medicine called ibogaine. At very low doses, these new compounds were able to blunt symptoms of both conditions in mice.

The study, published in Cell, took inspiration from ibogaine’s impact on the serotonin transporter (SERT), which is also the target of selective serotonin reuptake inhibitor (SSRI) drugs, such as fluoxetine. A team of scientists from UC San Francisco and Yale and Duke universities virtually screened 200 million molecular structures to find ones that blocked SERT in the same way as ibogaine.

“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the US,” said Brian Shoichet, PhD, co-senior author and professor in the UCSF School of Pharmacy. “Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behaviour, at least in mice.”

Dozens of scientists from the laboratories of Shoichet, Allan Basbaum, PhD, and Aashish Manglik, MD, PhD, (UCSF); Gary Rudnick, PhD, (Yale); and Bill Wetsel, PhD, (Duke) helped demonstrate the real-world promise of these novel molecules, which were initially identified using Shoichet’s computational docking methods.

Docking involves systematically testing virtual chemical structures for binding with a protein, enabling scientists to identify new drug leads without having to synthesise them in the lab. “This kind of project begins with visualizing what kinds of molecules will fit into a protein, docking the library, optimising and then relying on a team to show the molecules work,” said Isha Singh, PhD, a co-first author of the paper who did the work as a postdoc in Shoichet’s lab. “Now we know there’s a lot of untapped therapeutic potential in targeting SERT.”

Optimising a shaman’s cure

Ibogaine is found in the roots of the iboga plant, which is native to central Africa, and has been used for millennia during shamanistic rituals. In the 19th and 20th centuries, doctors in Europe and the US experimented with its use in treating a variety of ailments, but the drug never gained widespread acceptance and was ultimately made illegal in many countries.

Part of the problem, Shoichet explained, is that ibogaine interferes with many aspects of human biology.

“Ibogaine binds to hERG, which can cause heart arrhythmias, and from a scientific standpoint, it’s a ‘dirty’ drug, binding to lots of targets beyond SERT,” Shoichet said. “Before this experiment, we didn’t even know if the benefits of ibogaine came from its binding to SERT.”

Shoichet, who has used docking on brain receptors to identify drugs to treat depression and pain, became interested in SERT and ibogaine after Rudnick, an expert on SERT at Yale, spent a sabbatical in his lab. Singh picked up the project in 2018, hoping to turn the buzz around ibogaine into a better understanding of SERT.

It was the Shoichet lab’s first docking experiment on a transporter – a protein that moves molecules into and out of cells – rather than a receptor. One round of docking whittled the virtual library from 200 million to just 49 molecules, 36 of which could be synthesised. Rudnick’s lab tested them and found that 13 inhibited SERT.

The team then held virtual-reality-guided “docking parties,” to help Singh prioritise five molecules for optimization. The two most potent SERT inhibitors were shared with Basbaum and Wetsel’s teams for rigorous testing on animal models of addiction, depression and anxiety.

“All of a sudden, they popped – that’s when these drugs looked a lot more potent than even paroxetine [Paxil],” Shoichet said.

Manglik, an expert with cryo-electron microscopy (cryo-EM), confirmed that one of the two drugs, dubbed ‘8090,’ fit into SERT at the atomic level in a way that closely resembled Singh and Shoichet’s computational predictions. The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover impacts on a panel of hundreds of other receptors and transporters.

“With this sort of potency, we hope to have a better therapeutic window without side effects,” Basbaum said. “Dropping the dose almost 200-fold could make a big difference for patients.”

Source: University of California – San Francisco