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ENGineering extracellular matrix-based de novo proteins with high Affinity to Growth factors for Enhancing bone regeneration

Periodic Reporting for period 1 - ENGAGE (ENGineering extracellular matrix-based de novo proteins with high Affinity to Growth factors for Enhancing bone regeneration)

Reporting period: 2019-10-01 to 2020-09-30

Bone is a tissue that has the capacity to self-repair. However, in some circumstances such as big or complex fractures, or teeth missing, bone is not able to regenerate by itself. In these situations, biomaterials are being used to regenerate or substitute bone, although most of them do not induce proper bone regeneration. One strategy is the use of molecules secreted by cells, such as growth factors, that are immobilized onto the biomaterials in order to mimic the natural bone healing process. In this regard, Bone Morphogenetic Protein-2 (BMP-2) is a growth factor secreted by cells with potent bone regeneration capacities. Although its use in biomaterials has been shown promising results, the main problem is that BMP-2 is rapidly degraded upon implantation. Then, huge amounts of BMP-2 have to be implanted, which has been related to side effects such as inflammation or cancer.
Therefore, alternatives to BMP-2 are important for the society because they might be used to reduce or shorten the time recovery of patients that require a biomaterial implantation after bone fracture.
The overall objective of ENGAGE project is to computationally design a synthetic protein that will substitute BMP-2 and stimulate the same activity but with higher stability. Then, less amounts of the designed protein will be required for implantation, which is expected to reduce the undesired side effects associated to BMP-2.
Hundreds of thousands of candidates expected to have the same activity than BMP-2 have been computationally designed. The candidates have been computationally filtered to select the best among them, which have been tested in the laboratory to elucidate their affinity for the natural ligands of BMP-2 (the proteins located at the cell membrane that BMP-2 interacts with, inducing bone regeneration). Three candidates have been found with 1000 times more affinity than BMP-2 for their natural ligands.
Up to date, mutations of BMP-2 or short fragments derived from BMP-2 have been used to stimulate bone regeneration. However, mutations of BMP-2 are not sufficient to increase its stability while short fragments of BMP-2 do not stimulate bone regeneration at the same levels than BMP-2. To overcome these limitations, the computationally designed proteins in ENGAGE project are expected to strongly stimulate bone regeneration without eliciting side effects, as natural BMP2 does.
A computationally designed protein (green) interacting with a natural ligand of BMP-2 (blue)