PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Characterized drugs show unexpected effects

Known and yet unexpected: many active substances influence the cholesterol homeostasis and thereby possibly a SARS-CoV-2 infection

Characterized drugs show unexpected effects
2021-07-22
(Press-News.org) When Alexander Flemming discovered a mould on a culture plate overgrown with bacteria in 1928, he did not expect to find one of the most widely used active substances: penicillin. Accidental discoveries and the identification of active ingredients from traditional remedies, such as the morphine of the opium poppy, have shaped the discovery of new medicines for a long time.

Modern drug discovery - from chance to system

Meanwhile, major developments in chemistry and molecular biology have been made that enable a systematic and targeted search for potential active substances in modern drug discovery. First, advances in the field of organic and especially combinatorial chemistry made it possible to produce huge substance libraries and test them for their pharmacological effect in high-throughput tests. Following technological advances like the sequencing of the human genome and the development of new methods in molecular biology enabled the identification of disease-related cellular processes and their molecular key players. This paved the way towards modern drug discovery, where large libraries of molecules are screened in a high-throughput manner for their influence on relevant target molecules, mostly proteins. Identified substances, so-called hits, are optimized in their chemical structure to lead structures that are already effective in small doses and are well absorbed and distributed in the body.

No effect without side effects

This target-based drug development is very successful in identifying new drug candidates that prevent the target proteins from functioning or interacting with other proteins. However, potential drug candidates are rarely specific and very often also act on related proteins that have a similar function or structure. "It is not uncommon that an initially promising drug candidate unexpectedly shows serious side effects in a later phase of its longstanding development, thus limiting or even preventing its clinical use," says Slava Ziegler.

In search of unknown bioactivities

In order to track down possible side effects during drug development, potential drug candidates are screened in assays for their effect on known protein classes, biological processes and certain cellular properties. However, these tests can only reflect the expected bioactivity since the number of known target molecules in the cell is limited. So-called profiling approaches now offer the possibility of detecting a wider spectrum of activity. These unbiased tests investigate the influence on hundreds of cellular or genetic parameters recorded in a substance's profile that is compared with profiles of reference substances with known effects.

When drug profiles match

In their latest study, the group of Herbert Waldmann and Slava Ziegler combined two of these profiling approaches to identify bioactive substances from a library of about 15000 natural product-inspired molecules and compared them with the profiles of known, active compounds. Applying the Cell Painting Assay, where functional areas of the cell are stained and then microscopically examined for changes, a large cluster of substances with similar profiles was identified. However, it was not possible to predict the mode of action of the cluster since the associated reference compounds had various activities or target molecules. With a subsequent search using proteome profiling, in which the quantities and thus the regulation of thousands of proteins was examined, the researchers were able to narrow down the cluster to a common activity - the modulation of cholesterol homeostasis - an unexpected biological activity for the most reference substances in the cluster.

Two birds with one stone: identifying new bioactivities and side effects

But how can substances with very different target molecules trigger the same effect? The researchers revealed that most of the compounds in the cluster accumulate in the lysosome, an organelle where cholesterol is stored temporarily for its further function in the cell. The lysosome has a lower pH value than the rest of the cell, and this is crucial for the functioning of the lysosomal digestive enzymes that process foreign and the cell's own biomolecules. In the lysosome, the substances from the cluster described increase the pH value and thus disrupt the function of this organelle and, in particular, the cholesterol balance of the cell. The fact that the compounds accumulate in the lysosome is not due to a specific target molecule in the lysosome but to their chemical and physical properties, which they have obtained through their structural optimization for improved solubility.

"Interestingly, disturbed cholesterol balance has already been linked to some drugs on the market, such as antipsychotics" notes Tabea Schneidewind, first author of the study. " With the combination of the two search strategies, we can kill two birds with one stone: unveil unknown side effects and identify new active substances and modes of action" says Slava Ziegler.

Targeting cholesterol homeostasis could possibly also disturb SARS-CoV-2 infections

Influencing cholesterol homeostasis seems to be a common feature of many compounds and should be taken into account when evaluating side effects of active substances. However, the observed activity is not per se undesired. Currently, drugs and compounds with known modes of action are being intensively studied for inhibition of SARS-CoV-2 infection of host cells, and many compounds of our cluster have been identified to suppress this process. Interestingly, membrane cholesterol and thus proper cholesterol homeostasis are crucial for Sars-CoV-2 infection as shown in several studies. Our data most likely explain the reason for the activity of these compounds against the virus: they alter cholesterol biosynthesis and localization in cells, which impairs Corona-Virus infection", says Slava Ziegler.

INFORMATION:


[Attachments] See images for this press release:
Characterized drugs show unexpected effects

ELSE PRESS RELEASES FROM THIS DATE:

Rensselaer-designed platform could enable personalized immunotherapy

2021-07-22
TROY, N.Y. -- An innovative testing platform that more closely mimics what cancer encounters in the body may allow for more precise, personalized therapies by enabling the rapid study of multiple therapeutic combinations against tumor cells. The platform, which uses a three-dimensional environment to more closely mirror a tumor microenvironment, is demonstrated in research published in Communications Biology. "This whole platform really gives us a way to optimize personalized immunotherapy on a rapid, high throughput scale," said Jonathan Dordick, Institute Professor of chemical and biological engineering and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer Polytechnic Institute, ...

Excess coffee: A bitter brew for brain health

2021-07-22
It's a favourite first-order for the day, but while a quick coffee may perk us up, new research from the University of South Australia shows that too much could be dragging us down, especially when it comes to brain health. In the largest study of its kind, researchers have found that high coffee consumption is associated with smaller total brain volumes and an increased risk of dementia. Conducted at UniSA's Australian Centre for Precision Health at SAHMRI and a team of international researchers*, the study assessed the effects of coffee on the brain among 17,702 UK Biobank participants (aged 37-73), finding that those who drank more than six cups of coffee a day had a 53 per cent increased risk of dementia. Lead researcher and UniSA PhD candidate, ...

Silicon with a two-dimensional structure

Silicon with a two-dimensional structure
2021-07-22
Silicon, a semi-metal, bonds in its natural form with four other elements and its three-dimensional structure takes the form of a tetrahedron. For a long time, it seemed impossible to achieve the synthesis and characterisation of a two-dimensional equivalent - geometrically speaking, a square. Now scientists from the field of Inorganic Chemistry at Heidelberg University have succeeded in producing a crystalline complex with such a configuration. PD Dr Lutz Greb from the Institute of Inorganic Chemistry underlines that it has surprising physical and chemical properties and, in the field of molecular chemistry, will open up new approaches to using the second most abundant element in the Earth's crust for catalysis and materials research. As a classical ...

Smartphone screens effective sensors for soil or water contamination

2021-07-22
The touchscreen technology used in billions of smartphones and tablets could also be used as a powerful sensor, without the need for any modifications. Researchers from the University of Cambridge have demonstrated how a typical touchscreen could be used to identify common ionic contaminants in soil or drinking water by dropping liquid samples on the screen, the first time this has been achieved. The sensitivity of the touchscreen sensor is comparable to typical lab-based equipment, which would make it useful in low-resource settings. The researchers say their proof of concept could one day be expanded for a wide range of sensing applications, including for biosensing or medical diagnostics, right from the phone in your pocket. The results are reported ...

Infrared held in a pincer

2021-07-22
Many applications, from fiber-optic telecommunications to biomedical imaging processes require substances that emit light in the near-infrared range (NIR). A research team in Switzerland has now developed the first chromium complex that emits light in the coveted, longer wavelength NIR-II range. In the journal Angewandte Chemie, the team has introduced the underlying concept: a drastic change in the electronic structure of the chromium caused by the specially tailored ligands that envelop it. Many materials that emit NIR light are based on expensive or rare metal complexes. Cheaper alternatives that emit in the NIR-I range between 700 and 950 nm have been developed but NIR-II-emitting complexes of non-precious metals remain extremely rare. Luminescence in the NIR-II range (1000 to 1700 ...

Alzheimer-linked enzyme complex 'buckles up' for safe trip through the cell

2021-07-22
A research team led by Wim Annaert (VIB-KU Leuven) uncovered the early assembly of gamma-secretase, a protein complex linked to numerous cellular processes including the development of Alzheimer's disease. In a first step, two dimeric subcomplexes are formed, which independently exit the ER and only afterwards assemble into a four-subunit complex. This 'buckle up' mechanism is thought to prevent premature assembly and activity. The new insights are very relevant, as gamma-secretase is an important potential therapeutic target for Alzheimer's and other ...

HKU scientists harness the naturally abundant CRISPR-Cas system to edit superbugs with the hope of treating infections caused by drug resistant pathogens

HKU scientists harness the naturally abundant CRISPR-Cas system to edit superbugs with the hope of treating infections caused by drug resistant pathogens
2021-07-22
A research team led by Dr Aixin YAN, Associate Professor from the Research Division for Molecular & Cell Biology, Faculty of Science, in collaboration with Honorary Clinical Professor Patrick CY WOO from the Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong (HKU), reported the development of a transferrable and integrative type I CRISPR-based platform that can efficiently edit the diverse clinical isolates of Pseudomonas aeruginosa, a superbug capable of infecting various tissues and organs and a major source of nosocomial infections. The ...

NTU Singapore scientists develop tougher, safer bicycle helmets using new plastic material

NTU Singapore scientists develop tougher, safer bicycle helmets using new plastic material
2021-07-22
As cities worldwide expand their networks of cycling paths and more cyclists take to the streets, the chances of cycling accidents and potential collisions increase as well, underscoring the need for proper cycling safety in dense urban areas. According to a World Health Organisation report in 2020, more than 60 per cent of the reported bicycle-related deaths and long-term disabilities are a result of accidents with head injuries. Researchers from Nanyang Technological University, Singapore (NTU Singapore), in collaboration with French specialty materials leader Arkema, have developed a tougher, safer bicycle helmet using a combination of materials. The new helmet prototype has higher energy absorption, reducing the amount of energy ...

3D imaging reveals neural 'vicious cycle' in fatty liver disease

3D imaging reveals neural vicious cycle in fatty liver disease
2021-07-22
With the application of a novel three-dimensional imaging technology, researchers at Karolinska Institutet in Sweden have discovered that one portion of the autonomic nervous system in the liver undergoes severe degeneration in non-alcoholic fatty liver disease. The study, which is conducted in mice and human liver tissue, shows that the degeneration of nerves is correlated with the severity of liver pathology. The results are being published in the journal Science Advances. Non-alcoholic fatty liver disease is the most common hepatic disorder, with prevalence around 25 percent globally. Approximately ...

Visualizing a city's energy use

Visualizing a citys energy use
2021-07-22
The building sector in the U.S. accounts for 39 percent of energy use, with commercial buildings responsible for about half of that. As cities grapple with climate change, making commercial buildings more efficient is a key part of the solution. Researchers at the University of Pittsburgh Swanson School of Engineering and the Mascaro Center for Sustainable Innovation used the City of Pittsburgh to create a model built upon the design, materials and purpose of commercial buildings to estimate their energy usage and emissions. While other models may ...

LAST 30 PRESS RELEASES:

Heart rhythm disorder traced to bacterium lurking in our gums

American Society of Plant Biologists names 2025 award recipients

Protecting Iceland’s towns from lava flows – with dirt

Noninvasive intracranial source signal localization and decoding with high spatiotemporal resolution

A smarter way to make sulfones: Using molecular oxygen and a functional catalyst

Self-assembly of a large metal-peptide capsid nanostructure through geometric control

Fatty liver in pregnancy may increase risk of preterm birth

World record for lithium-ion conductors

Researchers map 7,000-year-old genetic mutation that protects against HIV

KIST leads next-generation energy storage technology with development of supercapacitor that overcomes limitations

Urine, not water for efficient production of green hydrogen

Chip-scale polydimethylsiloxane acousto-optic phase modulator boosts higher-resolution plasmonic comb spectroscopy

Blood test for many cancers could potentially thwart progression to late stage in up to half of cases

Women non-smokers still around 50% more likely than men to develop COPD

AI tool uses face photos to estimate biological age and predict cancer outcomes

North Korea’s illegal wildlife trade threatens endangered species

Health care workers, firefighters have increased PFAS levels, study finds

Turning light into usable energy

Important step towards improving diagnosis and treatment of brain metastases

Maternal cardiometabolic health during pregnancy associated with higher blood pressure in children, NIH study finds

Mercury levels in the atmosphere have decreased throughout the 21st century

This soft robot “thinks” with its legs

Biologists identify targets for new pancreatic cancer treatments

Simple tweaks to a gene underlie the stench of rotten-smelling flowers

Simple, effective interventions reduce emissions from Bangladesh’s informal brick kilns

Ultrasound-guided 3D bioprinting enables deep-tissue implant fabrication in vivo

Soft limbs of flexible tubes and air enable dynamic, autonomous robotic locomotion

Researchers develop practical solution to reduce emissions and improve air quality from brick manufacturing in Bangladesh

Durham University scientists solve 500-million-year fossil mystery

Red alert for our closest relatives

[Press-News.org] Characterized drugs show unexpected effects
Known and yet unexpected: many active substances influence the cholesterol homeostasis and thereby possibly a SARS-CoV-2 infection