New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of novel proteins targeting the hard-to-access cell membrane region.
March 13, 2024
LA JOLLA, CA Hitting targets embedded within the cell membrane has long been difficult for drug developers due to the membrane's challenging biochemical properties. Now, Scripps Research chemists have demonstrated new custom-designed proteins that can efficiently reach these intramembrane targets.
In their study, published March 13, 2024, in Nature Chemical Biology, the researchers used a unique computer-based approach to design novel proteins targeting the membrane-spanning region of the erythropoietin (EPO) receptor, which controls red blood cell production and can go awry in cancers. In addition to these new EPO-targeting molecules, the study yielded a general computational process, or workflow, for streamlining the flexible custom design of proteins aimed at intramembrane targets.
The researchers are now using their approach to develop potential new intramembrane-targeting treatments across a wide range of diseases.
This work opens up many new possibilities for the modulation of targets within the cell membrane, including for therapeutic applications and understanding signaling mechanisms across cell biology, says study co-corresponding author Marco Mravic, PhD, an assistant professor in the Department of Integrative Structural and Computational Biology at Scripps Research.
The study's other co-corresponding authors were Daniel DiMaio, MD, PhD, of the Yale School of Medicine; and William DeGrado, PhD, of the University of California, San Francisco School of Pharmacy, where Mravic was previously a PhD student.
A major goal of synthetic biology is to design proteins with biological activity here, we report the design and testing of a small protein that specifically perturbs the activity of a much larger protein receptor involved in blood cell growth and differentiation, says DiMaio, who is a professor of genetics and of molecular biophysics and biochemistry, and deputy director of Yale Cancer Center. We accomplished this by targeting the segment of the receptor that crosses the cell membrane. Because many cell proteins contain structurally conserved membrane-spanning segments, this general approach may be applicable to many other protein targets and provides a new tool to modulate the behavior of cells.
Hitting intramembrane targets has long been an important goal in biomedicine since many proteins in cells especially receptor proteins have functionally important domains inside the membrane. Such proteins have prominent roles in almost every area of health and disease.
Yet intramembrane targets are not ordinary targets. Cell membranes generally are made of two layers of tightly spaced, fat-related lipid molecules, which are water-repellent and have other unique and complex properties. This makes the intramembrane space a much harder target for drug designers, compared to the watery zones of cell surfaces or interiors.
There have been very few successful examples of drugs that target this space inside the membrane, Mravic says.
Those few successes, which include treatments for low-blood-platelet disorders and cystic fibrosis, have come from blind screenings of large compound libraries or from close mimicry of proteins known to interact with partner proteins within the cell membrane. By contrast, Mravic and colleagues set out to design completely novel proteins small ones called peptides to hit intramembrane protein targets in new and diverse ways. To do that, they had to extend the frontier of computational methods, combining data mining of known protein-to-protein interactions in membranes with traditional physics-based predictions of protein interactions.
Ultimately, Mravic and his colleagues designed the first proteins that bind the EPO receptor's membrane-spanning portion in a new way not seen in nature. The team showed that these proteins very specifically and potently block the receptor's function, in contrast to prior approaches.
The results may be of most immediate interest to researchers seeking new ways to inhibit the EPO receptor, which is often abnormally activated by tumor cells to maintain their growth and survival. But for Mravic and his colleagues, the study above all represents a proof of principle of a new and more flexible approach to intramembrane targeting.
We intend to use this approach to target membrane proteins across multiple biological processes and disease areas, including cancers, immune disorders, and pain, Mravic says.
He also expects the computational workflow he designed for the project to be a general accelerator of membrane-targeting drug design.
Before, the process basically involved two people in a dark room looking at a computer screen and saying, Yeah, I think this looks better than that,' Mravic says. Now, we've automated a lot of that molecule design process and decision making in the computer. Being more modular, flexible and streamlined allows the method to be more accessible for a broader range of scientists.
Mravic and his colleagues have posted their computational tools for public use on Github: https://github.com/mmravic314/CHAMP2023/.
De Novo Transmembrane Proteins Designed to Bind and Inhibit a Cytokine Receptor was co-authored by Marco Mravic, Li He, Huong Kratochvil, Hailin Hu, Sarah Nick, Weiya Bai, Anne Edwards, Hyunil Jo, Yibing Wu, Daniel DiMaio and William DeGrado.
Support for the research came from the National Institutes of Health (R35-122603, CA037157, GM68933) and the Howard Hughes Medical Institute.
Molecular and Cellular Biology Mravic, Marco
Most recent headlines
06/10/2025
France T l visions, France's leading broadcaster, has received the 2025 EBU ...
04/09/2025
Monumental Sports & Entertainment (MSE), in collaboration with Dalet, has been a...
30/08/2025
WASHINGTON The Federal Communications Commission has adopted its FY 2025 Regulatory Fees Order that establishes the regulatory fee rates for the broadcast stati...
29/08/2025
Australian Red Cross and SBS launch training to help workplaces in the fight aga...
29/08/2025
The National Film and Video Foundation (NFVF), an agency of the Department of Sp...
29/08/2025
L3Harris Technologies has concentrated decades of expertise across the entire enterprise to develop affordable and reliable best-of-breed solutions to rapidly c...
29/08/2025
BURBANK, Calif. The CW Network and the Pac-12 Conference have announced a new media rights deal that will extend their broadcast partnership beginning with the ...
29/08/2025
NEW YORK Gracenote has released a new analysis of its global video dataset showing that the number of FAST channels grew nearly 14% from Q1 2025 and 76% since 2...
29/08/2025
SAN JOSE, Calif. Harmonic has announced a series of improvements to its live sports streaming solution that the company said will improve fan engagement, protec...
29/08/2025
NEW YORK and LOS ANGELES Fox Corp. and YouTube TV last night announced a renewal of the full portfolio of Fox networks, including Fox News Channel, Fox Business...
29/08/2025
Budapest, Hungary, August 2025 - The integration of Microsoft Teams Rooms (MTR) with Lightware's Taurus universal matrix switchers delivers a new level of f...
29/08/2025
Frequency, the engine behind many of the world's best-known streaming television channels, today announced it will launch Studio Live, a next-generation uni...
29/08/2025
In an era when AI and cyber resilience are essential, Scality will mark the 10th anniversary of Scality Day on October 16, 2025 in Paris. This flagship global e...
29/08/2025
Disguise's In-House Creative and Technical Teams Pre-Visualised, Programmed and Delivered Content for the Experience, All Powered by EX 3+
Technology solu...
29/08/2025
Disguise will be demonstrating the latest workflows for TV, film and live events on a number of partner booths at the show
Disguise, the industry-leading tech...
29/08/2025
STOCKHOLM, Sweden Accedo will showcase Accedo Compose, its AI agent-powered modular orchestration layer that assists streaming providers in transitioning client...
29/08/2025
LOS ANGELES Cineverse has announced that it is working with Xperi to bring four of its streaming channels to automobiles for the first time as part of the DTS A...
29/08/2025
DALLAS & ATLANTA Gray Media has announced an agreement with the sports streaming service Victory+ to simulcast 17 Dallas Stars NHL games in 15 television market...
29/08/2025
NEW YORK AND CULVER CITY Comcast NBCUniversal and Amazon have announced new and extended distribution agreements that will expand the content available on their...
29/08/2025
FOOTHILL RANCH, Calif. RED Digital Cinema will feature its Cine-Broadcast Module supporting live broadcast workflows during IBC2025, Sept. 12-15, at the RAI Ams...
29/08/2025
29 Aug 2025
Kyivstar Rings Opening Bell at Nasdaq Marking Landmark Listing and ...
29/08/2025
More than half of all NFL games live on Sky for the first timeFriday 29 August 2025
Sky Sports has announced a new three-year deal with the NFL, extending its ...
29/08/2025
Back to All News
RIV4LRIES: The Trailer of the New Series With Samuele Carrino ...
29/08/2025
Get ready for an inspiring and emotional insight into the world of competitive Irish dancing with My Story: Tomi Champion of the World airing on RT 2 this monda...
29/08/2025
RT has today announced that David McCullagh is to be the new presenter of RT Radio 1's flagship Today programme, which airs every weekday at 10am, replaci...
28/08/2025
By Kristin Feeley, Director, Documentary Film & Artist Programs
If you want to tell untold stories, if you want to give voice to the voiceless, you've got ...
28/08/2025
Directed by Steven Bognar and Julia Reichert, Sundance Institute-supported Amer...
28/08/2025
Corridos have been a cornerstone of M sica Mexicana for generations, telling stories rooted in everyday life. Now, a new chapter is taking shape: motivational c...
28/08/2025
Los corridos han sido un pilar de la M sica Mexicana durante generaciones, contando historias enraizadas en la vida cotidiana. Ahora, un nuevo cap tulo est tom...
28/08/2025
Earlier this month, we promised our Verano Forever party would bring the heat, a...
28/08/2025
L3Harris will provide the Polish F-16V fleet with the Viper Shield electronic warfare system as part of an upgrade program....
28/08/2025
Bilbao, August 26, 2025 - AgileTV, an international television and video technol...
28/08/2025
Ken Wilkinson is an Emmy Awards nominated New York audio engineer who specialises in production sound mixing for film, commercial, episodic and documentary work...
28/08/2025
NEW YORK FuboTV today announced that it will launch Fubo Sports, a skinny bundle that focuses on sports with a subscription price of $56 monthly....
28/08/2025
NEVADA City, Calif. At IBC2025, Sept. 12-15 at the RAI Amsterdam, Telestream will debut its new Global Ingest strategy, introducing a next-generation ingest arc...
28/08/2025
Dr. Rhoda Bernard Releases Groundbreaking Debut Book on Accessible Arts Educatio...
28/08/2025
TAG Video Systems, the leader in software-based IP end-to-end workflow monitoring, deep probing, and real-time visualization, has named Oliver Gappa as Sales Di...
28/08/2025
AI-based voice enhancement will be among a series of innovations making their IBC 2025 debut on the DHD stand B46 in Hall 8 at the RAI Amsterdam Convention Cent...
28/08/2025
Telef nica Servicios Audiovisuales (TSA), the leading system integrator and service provider in the media sector in Spain, with the support of Appear, the globa...
28/08/2025
To fully immerse sailing fans in the world's biggest offshore yacht race, production company, Optical Media turned to LiveU's On-site Production solutio...
28/08/2025
Working with Calrec on its most recent overhaul, radio and television broadcaster, WNED has migrated to a fully IP infrastructure with multiple Type R consoles,...
28/08/2025
Cleeng, the Subscriber Retention Management (SRM ) inventor, has unveiled Cleeng Pro, the first-ever direct-to-consumer (D2C) subscription management platform t...
28/08/2025
Zixi, the industry leader in live broadcast-quality video over IP, today announced that French media distribution platform OKAST has selected Zixi to enable rel...
28/08/2025
Solution offers a streamlined, speaker-free architecture to optimize integration with premium external loudspeakers and advanced loudness metering
Nixer Pro Au...
28/08/2025
Cinegy, the premier provider of software-defined television technology, has announced a strategic partnership with Vision One Touch Film Production Services L.L...
28/08/2025
Telestream, a global leader in media workflow technologies, will debut its new Global Ingest strategy at IBC2025, introducing a next-generation ingest architect...
28/08/2025
Tier 1 operator selects Broadpeak to power high-performance, unified CDN solution across Norway, Sweden and Finland
Broadpeak, a leader in streaming and moneti...
28/08/2025
Leading video software provider, Synamedia, today announced that 24 Frames Digital, one of India's leading live event streaming service providers, has chose...
28/08/2025
Meet VisualOn at IBC2025: See What's Next in AI-Powered Video Streaming Join VisualOn at IBC2025 and discover how our AI-driven Optimizer and advanced media...
New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of novel proteins targeting the hard-to-access cell membrane region.
