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PROTEIN MISFOLDING OF INTEGRAL MEMBRANE PROTEINS

Welcome to ProMisMe

Bioengineered microbes as a platform for discovering chemical rescuers of disease-related misfolding of integral membrane proteins
THE PROJECT

The Project

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Protein misfolding lies at the heart of many devastating diseases. By targeting the root causes with precision and innovation, ProMisMe aims to transform the treatment landscape for patients suffering from these debilitating conditions and advance the frontiers of biomedical science forward. 

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Transforming the Landscape of Protein Misfolding Diseases

ProMisMe is a cutting-edge EU-funded research initiative dedicated to transform the landscape of Protein Misfolding Diseases (PMDs). Leveraging the latest breakthroughs in disease mechanism understanding and the innovative strides in biomolecular engineering and synthetic biology, ProMisMe is set to revolutionize therapeutic discovery for these elusive conditions.

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Pioneering Therapeutic Discovery

At ProMisMe, we are committed to developing groundbreaking technologies that pave the way for discovering potent therapeutic molecules. Our focus is on the misfolding-prone membrane proteins (MisMPs), a particularly challenging class of proteins and diseases that have notoriously been difficult to target.

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Harnessing Synthetic Biology for Innovation

ProMisMe harnesses the power of synthetic biology to create an innovative platform for the rapid production and screening of extensive libraries of cyclic oligopeptides. These emerging therapeutic molecules hold great promise in identifying inhibitors (rescuers) that can counteract the harmful misfolding of integral membrane proteins.

Specific Research Objectives

Protein misfolding lies at the heart of many devastating diseases. By targeting the root causes with precision and innovation, ProMisMe aims to transform the treatment landscape for patients suffering from these debilitating conditions and advance the frontiers of biomedical science forward. 

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Microbial Biosynthesis

Microbial biosynthesis of drug-like molecules libraries with greatly expanded diversities, enabling the synthesis of tens of millions to billions of different test molecules.

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Ultrahigh-Throughput Screening

Ultrahigh-throughput screening for the identification of chemical rescuers of disease-associated MP misfolding.

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Biochemical Evaluation

Evaluation of the effect of the selected molecules on MisMP folding and stability through biochemical and biophysical methods.

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Pathogenicity Testing

Evaluation of the effect of selected molecules on promoting the cell-surface accumulation of the target MPs in mammalian cell assays.
ProMisMe

PMDs

Protein misfolding diseases (PMDs) are a large group of human disorders caused by the misfolding of specific proteins. These diseases span a wide range of conditions that impact millions of lives, including Alzheimer’s disease, cystic fibrosis, obesity, and retinitis pigmentosa.

Different PMDs are associated with different proteins (soluble or membrane-bound, globular or intrinsically disordered etc.), they affect different organs (brain, lungs, heart, eyes etc.) and they present very distinct pathologies (neurodegeneration, heart failure, blindness etc.). Despite their differences, from the types of proteins involved to the organs they affect and the symptoms they cause, they all share a common molecular thread: protein misfolding.
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Usher Syndrome III

Usher Syndrome is a group of genetic conditions that affect both hearing and vision. Usher Syndrome III (USH3) is one of the three types of Usher Syndrome, characterized by progressive hearing loss, vision loss due to retinitis pigmentosa, and, in some cases, balance problems. While all types of Usher Syndrome share similar symptoms, USH3 tends to have a later onset and a more variable progression.
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Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders that affect the peripheral nerves, which are responsible for transmitting information and signals between the central nervous system and the rest of the body. Named after the three physicians who first identified it, CMT is one of the most common inherited nerve disorders, affecting approximately 1 in 2,500 people worldwide.
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Why It Matters

Protein misfolding lies at the heart of many devastating diseases. By targeting the root causes with precision and innovation, ProMisMe aims to transform the treatment landscape for patients suffering from these debilitating conditions and advance the frontiers of biomedical science forward. 

ProMisMe is dedicated to discovering therapeutic candidates for two severe PMDs: Usher Syndrome III and Charcot-Marie-Tooth disease. Success in this project will not only provide promising therapeutic leads against these major diseases but also establish a broadly applicable framework for drug discovery targeting various conditions caused by membrane protein misfolding.

ProMisMe

Our Approach

The primary objective of ProMisMe is to develop engineered yeast (Saccharomyces cerevisiae) that serve as discovery platform for compounds capable of rescuing MisMP misfolding. These compounds are sourced from vast libraries of drug-like molecules biosynthesized within these microbes, leveraging a technology that allows for the rapid production and screening of a vast diversity of test molecules. These libraries are screened in the microbial cells that produce them, and the molecules that effectively rescue MisMP misfolding are selected through ultrahigh-throughput screening.
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ProMisMe is funded by the “HORIZON TMA MSCA Postdoctoral Fellowships – European Fellowships” component of Horizon Europe Framework Programme (call Fostering balanced brain circulation “HORIZON-WIDERA-2022-TALENTS-04 – ERA Fellowships”), under Grant Agreement No. 101130862.

Useful Links

PMDs

Contact Info

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