THE NEW FRONTIER IN THE "DARK" PROTEOME
Many human diseases still do not have a cure or a meaningful treatment. Biomedical research characterizes the molecular cause of diseases that are the points of attack of drugs. The molecular causes of diseases are embodied by proteins that drive a set of biochemical reactions that form a chain of causation ("mechanism") leading to the disease. Human proteins are the products of genes, that is, they are encoded by DNA sequences. Proteins are the highly diverse parts of the complex machinery that operate all cell, tissue and body functions. Hence, undue activity of proteins causes diseases. Thus, proteins are the chief molecular targets of drugs. But only a tiny fraction of the human proteins is currently "druggable".
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We now realize that the space of all proteins encoded by the human genome, the proteome, is much larger than we have been thinking all along. The well-charted fraction of all the protein sequences in the genome contains those sequences that produce well-defined 3D protein structures. Knowledge of such 3D-shape of proteins have long afforded comfort in reasoning about the biological function of proteins function and has been the starting point for rational drug design. But beyond this well-illuminated portion of the proteome, a terra incognita, the "dark" proteome, populated by protein sequences that lack obvious 3D-structure, is now being explored. We have now learned: the absence of 3D-structure, which is needed to form the active (catalytic) site of proteins, does not mean lack of biological function.
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A goldrush to chart and exploit the dark proteome has started. The human proteome encompasses the 20,000 or so "canonical" proteins, those listed in databases, among which "druggable" targets can be identified. 40% of their sequences contain non-structured, disordered regions. But in addition, there are possibly 100,000s or more microproteins (peptides shorter than 100 amino acids) encoded in the genome that mostly do not form a stable defined 3D structure due to "intrinsic disorder" imposed by their peptide sequence. In both the canonical proteins and microproteins, these disordered regions mediate the formation of protein assemblies: well-defined protein complexes as well as large condensates that exert pivotal regulatory functions in cells and their organelles. In this newly expanded "dark" space of the proteome, thousands of proteins are now known to be "desirable targets" because their dysregulation drives disease processes, including cancer. But they are chemically undruggable due to their lack of defined structure. They are out of reach of current drug molecules.
To target the undruggable proteins, a rethink is needed. P4BIOS extends the current mode of thought in drug discovery beyond the paradigm of well-defined 3D- protein conformations of the druggable proteins. Their manipulation with drug molecules is based on this old paradigm: find a drug molecule that snuggly fits into pockets within such target proteins, like a key into a lock.
The guiding principle of P4BIOS' approach is to use its new discovery platform to target intrinsically disordered regions of canonical proteins and intrinsically disordered peptides, including microproteins and the shape-shiting proteins that exert powerful regulatory functions. Its neo-peptide drugs can also be intrinsically disordered - matching the natural language of protein interactions. P4BIOS opens a new frontier in drug research and drastically expands the target range of pharmacological intervention beyond the current 5% of the proteome - by exploring the undruggable dark proteome to develop drugs that target known or newly discovered hitherto undruggable disease-promoting proteins.