- Press Release Distribution

Membrane protein analogues could accelerate drug discovery

EPFL researchers have created a deep learning pipeline for designing soluble analogues of key protein structures used in pharmaceutical development, sidestepping the prohibitive cost of extracting these proteins from cell membranes.

Membrane protein analogues could accelerate drug discovery
( Many drug and antibody discovery pathways focus on intricately folded cell membrane proteins: when molecules of a drug candidate bind to these proteins, like a key going into a lock, they trigger chemical cascades that alter cellular behavior. But because these proteins are embedded in the lipid-containing outer layer of cells, they are tricky to access and insoluble in water-based solutions (hydrophobic), making them difficult to study.

"We wanted to get these proteins out of the cell membrane, so we redesigned them as hyperstable, soluble analogues, which look like membrane proteins but are much easier to work with,” explains Casper Goverde, a PhD student in the Laboratory of Protein Design and Immunoengineering (LPDI) in the School of Engineering.

In a nutshell, Goverde and a research team in the LPDI, led by Bruno Correia, used deep learning to design synthetic soluble versions of cell membrane proteins commonly used in pharmaceutical research. Whereas traditional screening methods rely on indirectly observing cellular reactions to drug and antibody candidates, or painstakingly extracting small quantities of membrane proteins from mammalian cells, the researchers’ computational approach allows them to remove cells from the equation. After designing a soluble protein analogue using their deep learning pipeline, they can use bacteria to produce the modified protein in bulk. These proteins can then bind directly in solution with molecular candidates of interest.

“We estimate that producing a batch of soluble protein analogues using E. coli is around 10 times less expensive than using mammalian cells,” adds PhD student Nicolas Goldbach.

The team’s research has recently been published in the journal Nature.

Flipping the script on protein design

In recent years, scientists have successfully harnessed artificial intelligence networks that use deep learning to design novel protein structures, for example by predicting them based on an input sequence of amino acid building blocks. But for this study, the researchers were interested in protein folds that already exist in nature; what they needed was a more accessible, soluble version of these proteins.

“We had the idea to invert this deep learning pipeline that predicts protein structure: if we input a structure, can it tell us the corresponding amino acid sequence?” explains Goverde.

To achieve this, the team used the structure prediction platform AlphaFold2 from Google DeepMind to produce amino acid sequences for soluble versions of several key cell membrane proteins, based on their 3D structure. Then, they used a second deep learning network, ProteinMPNN, to optimize those sequences for functional, soluble proteins. The researchers were pleased to discover that their approach showed remarkable success and accuracy in producing soluble proteins that maintained parts of their native functionality, even when applied to highly complex folds that have so far eluded other design methods. 

“The holy grail of biochemistry”

A particular triumph of the study was the pipeline’s success in designing a soluble analogue of a protein shape known as the G-protein coupled receptor (GPCR), which represents around 40% of human cell membrane proteins and is a major pharmaceutical target.

“We showed for the first time that we can redesign the GPCR shape as a stable soluble analogue. This has been a long-standing problem in biochemistry, because if you can make it soluble, you can screen for novel drugs much faster and more easily,” says LPDI scientist Martin Pacesa.

The researchers also see these results as a proof-of-concept for their pipeline’s application to vaccine research, and even cancer therapeutics. For example, they designed a soluble analogue of a protein type called a claudin, which plays a role in making tumors resistant to the immune system and chemotherapy. In their experiments, the team’s soluble claudin analogue retained its biological properties, reinforcing the pipeline’s promise for generating interesting targets for pharmaceutical development.


[Attachments] See images for this press release:
Membrane protein analogues could accelerate drug discovery


Berkeley Lab researchers advance AI-driven plant root analysis

Berkeley Lab researchers advance AI-driven plant root analysis
In a world striving for sustainability, understanding the hidden half of a living plant – the roots – is crucial. Roots are not just an anchor; they are a dynamic interface between the plant and soil, critical for water uptake, nutrient absorption, and, ultimately, the survival of the plant. In an investigation to boost agricultural yields and develop crops resilient to climate change, scientists from Lawrence Berkeley National Laboratory’s (Berkeley Lab’s) Applied Mathematics and Computational Research (AMCR) and Environmental Genomics and Systems Biology (EGSB) Divisions have made a significant leap. Their latest innovation, RhizoNet, harnesses the power ...

Cleveland Clinic study shows weight loss surgery cuts risk of heart complications and death in patients with obstructive sleep apnea and obesity

Press release under embargo: Cleveland Clinic Study Shows Weight Loss Surgery Cuts Risk of Heart Complications and Death in Patients with Obstructive Sleep Apnea and Obesity  First-of-its-kind MOSAIC study shows weight-loss surgery is associated with a 42% reduction in risk of heart complications and 37% reduction in risk of death in patients with obstructive sleep apnea   Under embargo until Friday, June 21, 2024, 9:00 AM ET, CLEVELAND: A Cleveland Clinic study shows that bariatric surgery performed in patients with obesity and moderate to severe obstructive sleep apnea is associated with a significantly lower risk of ...

SQUID pries open AI black box

SQUID pries open AI black box
Artificial intelligence continues to squirm its way into many aspects of our lives. But what about biology, the study of life itself? AI can sift through hundreds of thousands of genome data points to identify potential new therapeutic targets. While these genomic insights may appear helpful, scientists aren’t sure how today’s AI models come to their conclusions in the first place. Now, a new system named SQUID arrives on the scene armed to pry open AI’s black box of murky internal logic. SQUID, ...

Resiliency shaped by activity in the gut microbiome and brain

A new UCLA Health study has found that resilient people exhibit neural activity in the brain regions associated with improved cognition and regulating of emotions, and were more mindful and better at describing their feelings. The same group also exhibited gut microbiome activity linked to a healthy gut, with reduced inflammation and gut barrier. For the study, rather than examine microbiome activity and composition linked to disease conditions-- like anxiety and depression -- the researchers wanted to flip the script and study the gut microbiome and brain in healthy, resilient people who effectively cope with different types of stress, including discrimination ...

Inspired by nature: synthetic nightshade molecule effective against leukemia cells

Inspired by nature: synthetic nightshade molecule effective against leukemia cells
Nightshade plants produce a diverse array of compounds with therapeutic potential. Researchers at CeMM have now identified an artificial variant inspired by the Withanolides group that acts highly specifically against leukemia cells. Using state-of-the-art chemical and genetic high-throughput analyses, the team led by Georg Winter not only confirmed its effectiveness but also elucidated its mechanism of action: the molecule disrupts the cholesterol metabolism of tumor cells. The study's findings ...

Promise green hydrogen may not always be fulfilled

Green hydrogen often, but certainly not always, leads to CO2 gains. This claim is based on research published in Nature Energy by Kiane de Kleijne from Radboud University and Eindhoven University of Technology. “If you calculate the entire life cycle of green hydrogen production and transport, CO2 gains may be disappointing. However, if green hydrogen is produced from very clean electricity and locally, it can really help reduce emissions.” It is thought that green hydrogen can make ...

Unifying behavioral analysis through animal foundation models

Unifying behavioral analysis through animal foundation models
Although there is the saying, “straight from the horse’s mouth”, it's impossible to get a horse to tell you if it's in pain or experiencing joy. Yet, its body will express the answer in its movements. To a trained eye, pain will manifest as a change in gait, or in the case of joy, the facial expressions of the animal could change. But what if we can automate this with AI? And what about AI models for cows, dogs, cats, or even mice? Automating animal behavior not only removes observer bias, but it helps humans more efficiently get to the right answer. Today ...

Up to 30 percent more time: Climate change makes it harder for women to collect water

Climate change could increase the amount of time women spend collecting water by up to 30 percent globally by 2050, according to a new study published in Nature Climate Change. In regions of South America and Southeast Asia, the time spent collecting water could double due to higher temperatures and less rainfall. A team of scientists from the Potsdam Institute for Climate Impact Research (PIK) estimates the large welfare losses that could result from climate impacts and highlights how women are particularly vulnerable to changing future climate conditions. Worldwide, two billion people currently lack access to safe drinking water. The ...

Heart failure in space: scientists calculate potential health threats facing future space tourists in microgravity

Heart failure in space: scientists calculate potential health threats facing future space tourists in microgravity
[The following is a guest editorial written by Dr Lex van Loon, an assistant professor at the Australian National University and the University of Twente in the Netherlands. He is co-author of a new Frontiers in Physiology article.] Space exploration has always captivated our imagination, offering the promise of discovering new worlds and pushing the boundaries of human capability. As commercial space travel becomes more accessible, individuals with various underlying health conditions—including heart failure—may soon be among those venturing beyond Earth’s atmosphere. This raises critical questions about the impact of space travel ...

Experts offer guidance on talking with children about racism at pediatrician's office

Extensive research shows the link between exposure to racism during childhood and adolescence and increased risks of depression and metabolic health issues, such as obesity, diabetes and heart disease. Conversely, racial socialization, described as behaviors and practices that teach children about race and ethnic identity, has shown potential in mitigating these negative effects, and discussions like these could be effective in pediatric clinics, according to the first expert consensus guidance on this topic published in Pediatrics. “Over the years, numerous calls to action have been made to address racism in medicine. ...


Duke-NUS launches LIVE Ventures, a S$20 million incubator to accelerate research commercialisation

Samuel Pepys’ fashion prints reveal his guilty pleasure: Fancy French clothes

New genetic test will eliminate a form of inherited blindness in dogs

Cancer risk: Most Australian welders exposed to high levels of dangerous fumes

Two-in-one mapping of temperature and flow around microscale convective flows

Texas A&M engineers explore intelligence augmentation to improve safety

ORNL economist honored at international hydropower conference

UCLA selected by Centers for Medicare & Medicaid Services to test Medicare dementia care model

Fish adjust reproduction in response to predators

DDX41 and its unique contribution to myeloid leukemogenesis

Digital games on vaping devices could lure more youth to nicotine addiction

Cracking the code of hydrogen embrittlement

Long-term results from Testicular Cancer treatment are positive, study shows

EPA awards UMass Amherst nearly $6.4 million to help shrink the steel industry’s carbon footprint

Valentina Greco takes on new position as President of the ISSCR

Komen supports UVA Engineering researchers targeting ‘triple negative' breast cancer

Panel issues first guidelines to prevent anal cancer in people with HIV

Estimating rainfall intensity using surveillance audio and deep-learning

Targeting factors for chemoprevention and cancer interception to tackle mesothelioma

New snake discovery rewrites history, points to North America’s role in snake evolution

Large and unequal life expectancy declines in India during COVID-19

A study of 156,000 UK residents found that urban residents score the lowest in social and economic satisfaction and well-being

Global study by Hawaiʻi Institute of Marine Biology demonstrates benefit of marine protected areas to recreational fisheries

Researchers clarify how soft materials fail under stress

Revolutionizing the abilities of adaptive radar with AI

Plastic waste can now be converted to electronic devices

Health equity scholar Darrell Hudson named Health Behavior and Health Education chair at the University of Michigan School of Public Health

Research will establish best ‘managed retreat’ practices for communities faced with climate change disaster

Marshall University awarded grant to further fentanyl addiction research

Wash U researchers shine light on amyloid architecture

[] Membrane protein analogues could accelerate drug discovery
EPFL researchers have created a deep learning pipeline for designing soluble analogues of key protein structures used in pharmaceutical development, sidestepping the prohibitive cost of extracting these proteins from cell membranes.