The design, structures and therapeutic potential of protein epitope mimetics

Robinson, John A.; DeMarco, Steve; Gombert, Frank O.; Moehle, Kerstin; Obrecht, Daniel

doi:10.1016/j.drudis.2008.07.008

Cited by 130 publications

(98 citation statements)

References 68 publications

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“…The knowledge of relevant interactions and their space relationships in the stabilization of protein⅐protein complexes may thereby boost our ability to interfere with specific protein-protein interactions, providing attractive therapeutic opportunities and extending medicinal chemistry to new classes of compounds. Different rational approaches are in fact based on the identification of synthetic molecules that mimic the hot spot interactions in relevant macromolecular complexes (20,23,24). Computational biology methods based on all-atom molecular dynamics (MD) have recently proved successful in identifying the functional and conformational determinants of molecular recognition and translating these models into novel antagonists with specific activities, thus expanding the molecular diversity space of mimics of interacting active sequences (25)(26)(27)(28)(29).…”

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confidence: 99%

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Colombo

Margosio

Ragona

et al. 2010

Journal of Biological Chemistry

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Endogenous inhibitors of angiogenesis, such as thrombospondin-1 (TSP-1), are promising sources of therapeutic agents to treat angiogenesis-driven diseases, including cancer. TSP-1 regulates angiogenesis through different mechanisms, including binding and sequestration of the angiogenic factor fibroblast growth factor-2 (FGF-2), through a site located in the calcium binding type III repeats. We hypothesized that the FGF-2 binding sequence of TSP-1 might serve as a template for the development of inhibitors of angiogenesis. Using a peptide array approach followed by binding assays with synthetic peptides and recombinant proteins, we identified a FGF-2 binding sequence of TSP-1 in the 15-mer sequence DDDDDNDKIPD-DRDN. Molecular dynamics simulations, taking the full flexibility of the ligand and receptor into account, and nuclear magnetic resonance identified the relevant residues and conformational determinants for the peptide-FGF interaction. This information was translated into a pharmacophore model used to screen the NCI2003 small molecule databases, leading to the identification of three small molecules that bound FGF-2 with affinity in the submicromolar range. The lead compounds inhibited FGF-2-induced endothelial cell proliferation in vitro and affected angiogenesis induced by FGF-2 in the chicken chorioallantoic membrane assay. These small molecules, therefore, represent promising leads for the development of antiangiogenic agents. Altogether, this study demonstrates that new biological insights obtained by integrated multidisciplinary approaches can be used to develop small molecule mimics of endogenous proteins as therapeutic agents.Inhibitors of angiogenesis, aimed at preventing the deregulated formation of new blood vessels, are emerging as a successful approach to treat an array of diseases, including cancer (1). Antiangiogenic strategies are designed to reestablish the balance between angiogenic factors and endogenous inhibitors, restoring the physiologically quiescent condition of the vasculature (2). A strategy to achieve this is to exploit the activity of endogenous inhibitors of angiogenesis (3).Thrombospondin-1 (TSP-1) 2 was the first endogenous inhibitor of angiogenesis identified (4, 5). Of the five members that constitute the TSP family in mammals, the homotrimeric TSP-1 and TSP-2 share domain organization and the ability to inhibit angiogenesis. Like other thrombospondins, TSP-1 is a multi-modular protein. Each monomer consists of an N-terminal globular domain followed by the coiled-coil oligomerization domain, a von Willebrand factor type C repeat, three properdin-like type I repeats, two TSP-type epidermal growth factor (EGF)-like or type II repeats, and a signature domain comprising a third EGF-like repeat, the calcium binding wire or type III repeats, and the lectin-like C-terminal globular domain (6).TSP-1 has been classified functionally as a matricellular protein, i.e. an extracellular protein that acts to regulate cell interactions with the environment (7). TSP-1 binds to a variety of ...

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confidence: 99%

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Colombo

Margosio

Ragona

et al. 2010

Journal of Biological Chemistry

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“…Based on the solution structure of polyphemusin II, several PEM molecules were designed and optimized in biological assays. This led to highly potent and selective CXCR4 antagonist such as POL3026, POL5551 and POL6326 (DeMarco et al 2006;Robinson et al 2008). POL6326 has now successfully moved into a phase II clinical trial for autologous stem cell transplantation in newly diagnosed multiple myeloma patients.…”

Section: ß-Hairpin Mimeticsmentioning

confidence: 99%

17 The protein epitope mimetic approach to protein-protein interaction inhibitors

Moehle¹,

Tschesche²

2011

Methods in Protein Biochemistry

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“…[63][64][65][66][67] An important group of conformationally constrained dipeptide analogues are azabicycloalkane amino acids, comprising various saturated fused heterocycles with a bridgehead nitrogen atom. [68][69][70] 6-Amino-7-oxotetrahydropyrazolo[1,2-a]pyrazole-1-carboxylic acid (40) based scaffolds are a subgroup of 5,5-fused azabicycloalkane amino acids.…”

Section: Pyrazolo[12-a]pyrazolesmentioning

confidence: 99%

Recent advances in the synthesis of polysubstituted 3-pyrazolidinones

Grošelj¹,

Svete²

2015

Arkivoc

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An account of recent developments in the field of 3-pyrazolidinone chemistry is given with special focus on the synthesis and transformations of 5-substituted 4-benzyloxycarbonylamino-3-pyrazolidinones, pyrazolo[1,2-a]pyrazole-based peptide analogues, and tetrahydropyrazolo-[1,5-c]pyrimidine-2,7-diones. In terms of practical application, polyfunctionalized 3-pyrazolidinones as 'aza-deoxa' analogues of cycloserine, peptide mimetics based on 3-amino-2-oxo-1,5-diazabicyclo[3.3.0]octane-7-carboxylic acid, and 1,6-disubstituted tetrahydropyrazolo[1,5-c]-pyrimidine-2,7-diones as the first representatives of a novel saturated heterocyclic system were prepared by these newly developed synthetic methods.

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The design, structures and therapeutic potential of protein epitope mimetics

Cited by 130 publications

References 68 publications

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

Non-peptidic Thrombospondin-1 Mimics as Fibroblast Growth Factor-2 Inhibitors

17 The protein epitope mimetic approach to protein-protein interaction inhibitors

Recent advances in the synthesis of polysubstituted 3-pyrazolidinones

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