Structural definition of the discrete hotspot sites of BMP-2 conformational wrist epitope and rational design of the hotspot-derived osteogenic peptides against chondrocyte senescence

Zhang, Wei; Liu, Jiazhi; Zhang, Chi; Yu, Xiaowei; Zhong, Biao

doi:10.1016/j.bioorg.2021.105382

Cited by 6 publications

(4 citation statements)

References 43 publications

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“…All experiments were carried out at 25°C and each assay was performed in triplicate. The dissociation constants ( K d ) were determined by fitting titration curves to the equation 49 :

f = [f_{0} + f_{\infty} ([P] / K_{normald})] / [1 + ([P] / K_{normald})],

where [ P ] is protein concentration, f is the observed anisotropy at the concentration, f 0 is the anisotropy when concentration = 0, and f ∞ is the maximal anisotropy saturated concentration.…”

Section: Methodsmentioning

confidence: 99%

Structure‐based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL‐5R/IL‐5 interaction by gluing halogen bonds at their complex interface

Chu,

Sheng,

Shen

et al. 2023

J of Molecular Recognition

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Human interleukin‐5 (IL‐5) cytokine mediates the development of eosinophils and is involved in a variety of immune inflammatory responses that play a major role in the pathogenesis of childhood asthma, leukemia, and other pediatric allergic diseases. The immunomodulatory cytokine functions by binding to its cognate cell surface receptor IL‐5R in a sheet‐by‐sheet manner, which can be conformationally mimicked and competitively disrupted by a double‐stranded cyclic AF18748 peptide. In this study, we systematically examined the co‐crystallized complex structure of human IL‐5R with AF18748 peptide and rationally designed a halogen bond to glue at the protein–peptide complex interface by substituting the indole moiety of AF18748 Trp13 residue with a halogen atom (X = F, Cl, Br, or I). High‐level theoretical calculations imparted presence of the halogen bond between the oxygen atom (O) of IL‐5R Glu58 backbone and the halogen atom (X) of AF18748 Trp13 side chain. Experimental assays confirmed that the halogen bond can promote peptide binding moderately or considerably. More importantly, the halogen bond not only enhances peptide affinity to IL‐5R, but also improves peptide selectivity for its cognate IL‐5R over other noncognate IL‐R proteins. As might be expected, the affinity and selectivity conferred by halogen bond increase consistently in the order: H < F < Cl < Br < I. Structural modeling revealed that the halogen bond plus its vicinal π–cation–π stacking co‐define a ringed noncovalent system at the complex interface, which involves a synergistic effect to effectively improve the peptide binding potency and recognition specificity.

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“…All experiments were carried out at 25°C and each assay was performed in triplicate. The dissociation constants ( K d ) were determined by fitting titration curves to the equation 49 :

f = [f_{0} + f_{\infty} ([P] / K_{normald})] / [1 + ([P] / K_{normald})],

Section: Methodsmentioning

confidence: 99%

Structure‐based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL‐5R/IL‐5 interaction by gluing halogen bonds at their complex interface

Chu,

Sheng,

Shen

et al. 2023

J of Molecular Recognition

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“…Peptide‐functionalized hydrogels also feature a high degree of control over peptide concentration and location, and hydrogels formed with rhBMP‐2 mimetic peptides can maximize the therapeutic properties of rhBMP‐2 while minimizing off‐target effects. The rhBMP‐2 protein has two osteogenic receptor‐binding regions that bind to BMP receptor I (BMPR‐I) and BMP receptor II (BMPR‐II), known as the wrist and knuckle epitopes, respectively 23–25 . The DWIVA peptide sequence derived from the knuckle epitope of rhBMP‐2 also has high binding affinity towards BMPR‐I, and several studies have demonstrated that DWIVA‐modified hydrogels induce osteogenic differentiation in vitro and in vivo 22,26 …”

Section: Introductionmentioning

confidence: 99%

“…The rhBMP-2 protein has two osteogenic receptor-binding regions that bind to BMP receptor I (BMPR-I) and BMP receptor II (BMPR-II), known as the wrist and knuckle epitopes, respectively. [23][24][25] The DWIVA peptide sequence derived from the knuckle epitope of rhBMP-2 also has high binding affinity towards BMPR-I, and several studies have demonstrated that DWIVA-modified hydrogels induce osteogenic differentiation in vitro and in vivo. 22,26 Our group recently developed injectable hydrogels based on a Diels Alder reaction between norbornene and tetrazine modified hyaluronic acid macromers.…”

mentioning

confidence: 99%

Mesenchymal stem cells enhance targeted bone growth from injectable hydrogels with BMP‐2 peptides

Love,

Gultian,

Jalloh

et al. 2024

Journal Orthopaedic Research

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Osteoporosis is the most common chronic metabolic bone disease, and the prevalence of osteoporotic fractures is rapidly increasing with the aging population. While bisphosphonates can reduce bone loss and risk of fracture, these drugs are systemic, rely on long‐term use, and patient compliance is low. Recombinant human bone morphogenetic protein‐2 (BMP‐2) is an FDA‐approved protein that can offer a more targeted therapeutic than systemic treatments. DWIVA is a peptide sequence corresponding to the wrist epitope of BMP‐2, and DWIVA‐functionalized hydrogels feature osteoinductive propertiesin vitro and in vivo. This study reports that self‐forming DWIVA‐functionalized hydrogels injected into the intramedullary canal of rat femurs induce a local increase in trabecular bone in as little as 2 weeks. Increases in bone volume, trabecular thickness, and trabeculae count from DWIVA‐laden hydrogels persist for at least 4 weeks, and the inclusion of mesenchymal stem cells (MSCs) significantly enhances the development of mineralized bone. Histological analysis of decalcified femurs also shows that hydrogel injections containing DWIVA peptide and MSCs stimulate unmineralized bone tissue formation and induce an increased count of osteoblasts and osteoclasts at the injection site after 4 weeks. Overall, the MSC‐laden DWIVA peptide‐functionalized hydrogels presented rapidly induce targeted bone formation and have the potential to form nascent bone within bones in jeopardy of an osteoporotic fracture such as the femur.

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“…[30,31] In particular, a peptidic fragment derived from the knuckle epitope of BMP-2 (spanning residues 73-92 -KIPKASSVPTELSAISTLYL), which binds to BMP receptor type II, [32] promotes osteodifferentiation. [33] On the other hand, the wrist epitope (amino acids 30-34 -DWIVA), which primarily interacts with BMP receptor type I, [34] has also been identified and demonstrated to display osteogenic potential. [35] Based on the rationale discussed above, these BMP-2 domains may be integrated with RGD-based ligands to induce integrin/GF signaling without the need of using GFs.…”

Section: Introductionmentioning

confidence: 99%

Mimicking Bone Extracellular Matrix: From BMP‐2‐Derived Sequences to Osteogenic‐Multifunctional Coatings

Oliver‐Cervelló

Martin‐Gómez

Mandakhbayar

et al. 2022

Adv Healthcare Materials

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Cell-material interactions are regulated by mimicking bone extracellular matrix on the surface of biomaterials. In this regard, reproducing the extracellular conditions that promote integrin and growth factor (GF) signaling is a major goal to trigger bone regeneration. Thus, the use of synthetic osteogenic domains derived from bone morphogenetic protein 2 (BMP-2) is gaining increasing attention, as this strategy is devoid of the clinical risks associated with this molecule. In this work, the wrist and knuckle epitopes of BMP-2 are screened to identify peptides with potential osteogenic properties. The most active sequences (the DWIVA motif and its cyclic version) are combined with the cell adhesive RGD peptide (linear and cyclic variants), to produce tailor-made biomimetic peptides presenting the bioactive cues in a chemically and geometrically defined manner. Such multifunctional peptides are next used to functionalize titanium surfaces. Biological characterization with mesenchymal stem cells demonstrates the ability of the biointerfaces to synergistically enhance cell adhesion and osteogenic differentiation. Furthermore, in vivo studies in rat calvarial defects prove the capacity of the biomimetic coatings to improve new bone formation and reduce fibrous tissue thickness. These results highlight the potential of mimicking integrin-GF signaling with synthetic peptides, without the need for exogenous GFs.

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Structural definition of the discrete hotspot sites of BMP-2 conformational wrist epitope and rational design of the hotspot-derived osteogenic peptides against chondrocyte senescence

Cited by 6 publications

References 43 publications

Structure‐based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL‐5R/IL‐5 interaction by gluing halogen bonds at their complex interface

Structure‐based improvement of the binding affinity and recognition specificity of peptide competitors to target pediatric IL‐5R/IL‐5 interaction by gluing halogen bonds at their complex interface

Mesenchymal stem cells enhance targeted bone growth from injectable hydrogels with BMP‐2 peptides

Mimicking Bone Extracellular Matrix: From BMP‐2‐Derived Sequences to Osteogenic‐Multifunctional Coatings

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