A Process for the Design and Development of Novel Bone Morphogenetic Protein-7 (BMP-7) Mimetics With an Example: THR-184

Abstract

Growth Factors have been evaluated as therapeutic targets for the treatment of a broad spectrum of diseases. Because they are proteins with pleiotropic effects, the quest to harness their beneficial effects has presented challenges. Most Growth Factors operate at the extracellular-receptor level and have natural feedback mechanisms that modulate their effects. As proteins, they are difficult and expensive to manufacture. Frequently proteins must be administered parenterally, may invoke an immune response, and may be neutralized by naturally occurring inhibitors. To circumvent these limitations, we have undertaken an effort to develop mimetics for the Bone Morphogenetic Protein (BMP) signaling pathway effects that incorporate the beneficial effects, eliminate the deleterious effects, and thereby create effective drug-like compounds.To this end, we have designed and tested a family of small peptide BMP mimetics. The design used the three-dimensional structure of BMP-7 to identify likely active surface regions. Lead sequences were then optimized based on in vitro assays that examine the selective binding to BMP receptors, demonstrate the phosphorylation of Smad-1,5,8, detect anti-apoptosis and anti-inflammation, and block the epithelial to mesenchymal transition (EMT) in renal tubular epithelial cells. These sequences were further optimized using in vivo assays of the attenuation of acute kidney injury in a rat-model of unilateral clamp ischemic reperfusion. This process uses a Structure Variance Analysis algorithm (SVA) to identify structure/activity relationships. One member of this family, THR-184, is an agonist of BMP signaling and a potent antagonist of TGFβ signaling. This small peptide mimetic inhibits inflammation, apoptosis, fibrosis and reverses epithelial to mesenchymal transition (EMT) by regulating multiple signaling pathways involved in the cellular injury of multiple organs. Its effects have been shown to control Acute Kidney Injury (AKI). THR-184 has progressed through phase I and II clinical trials for the prevention of Cardio-Vascular Surgery (CVS) associated AKI. This work provides a roadmap for the development of other growth factor mimetics and demonstrates how we might harness their therapeutic potential.

Control of neuronal excitation–inhibition balance by BMP–SMAD1 signalling

“…Disruptions in the excitation–inhibition balance and homeostatic adaptations have been implicated in neurodevelopmental disorders, and reduced GABAergic signalling and a propensity to develop epilepsy are often seen in individuals with autism 3 – 5 , 52 . Considering that BMP signalling pathways can be targeted with peptide mimetics 53 , these might provide an entry point for therapeutic interventions in neurodevelopmental disorders that are characterized by disruptions in the innervation of PV interneurons, the excitation–inhibition balance and seizures.…”

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

“…Disruptions in excitation -inhibition balance and homeostatic adaptations have been implicated in neurodevelopmental disorders as there is reduced GABAergic signaling and a propensity to develop epilepsy in individuals with autism [49][50][51]54 . Considering that BMPsignaling pathways can be targeted with peptide mimetics 55…”

“…Disruptions in excitation – inhibition balance and homeostatic adaptations have been implicated in neurodevelopmental disorders as there is reduced GABAergic signaling and a propensity to develop epilepsy in individuals with autism 54–56,59 . Considering that BMP-signaling pathways can be targeted with peptide mimetics 60 they may provide an entry point for therapeutic interventions in neurodevelopmental disorders characterized by disruptions in PV interneuron innervation, excitation – inhibition balance, and seizures.…”

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

“…These are exclusively represented by protein or peptide modalities, which are beyond the scope of this Review. To provide a brief overview, a variety of BMP mimetic peptides were designed based on crystal structures of BMPs or BMP receptors. − Notably, THR-184 was tested in phase 1 and phase 2 clinical trials for the prevention of cardio­vascular-associated acute kidney injury, where it demonstrated safety but no significant efficacy. , “BMP activators” also act on the receptor level; they do not mimic ligands but rather enhance the activation of downstream signaling effectors. As the largest and most diverse set, we categorized “BMP potentiators” that increase cellular responsiveness to BMP, typically dependent on at least low-level basal pathway activity.…”

“…90−93 Notably, THR-184 was tested in phase 1 and phase 2 clinical trials for the prevention of cardiovascular-associated acute kidney injury, where it demonstrated safety but no significant efficacy. 90,94 "BMP activators" also act on the receptor level; they do not mimic ligands but rather enhance the activation of downstream signaling effectors. As the largest and most diverse set, we categorized "BMP potentiators" that increase cellular responsiveness to BMP, typically dependent on at least low-level basal pathway activity.…”