Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

Johnson, Dana L.; Farrell, Francis X.; Barbone, Francis P.; McMahon, Frank J.; Tullai, Jennifer; Kroon, Daniel J.; Freedy, James; Zivin, Robert A.; Mulcahy, Linda S.; Jolliffe, Linda K.

doi:10.1016/s1074-5521(97)90302-1

Cited by 53 publications

(48 citation statements)

References 23 publications

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“…Polyvalency has even been explored for biological signaling initiated by receptor dimerization, as is the case for VEGF receptor signaling. Examples include synthetic multivalent mimics of erythropoietin and thrombopoietin, both of which require receptor dimerization that is enhanced by multivalent signals (47,48). Native VEGF, as a homodimeric cysteine knot protein, is multivalent (specifically divalent) with two bioactive domains that interact with receptor dimers (3), a feature that is not recreated in the soluble VEGF peptide mimic.…”

Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

295

268

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There is great demand for the development of novel therapies for ischemic cardiovascular disease, a leading cause of morbidity and mortality worldwide. We report here on the development of a completely synthetic cell-free therapy based on peptide amphiphile nanostructures designed to mimic the activity of VEGF, one of the most potent angiogenic signaling proteins. Following self-assembly of peptide amphiphiles, nanoscale filaments form that display on their surfaces a VEGF-mimetic peptide at high density. The VEGF-mimetic filaments were found to induce phosphorylation of VEGF receptors and promote proangiogenic behavior in endothelial cells, indicated by an enhancement in proliferation, survival, and migration in vitro. In a chicken embryo assay, these nanostructures elicited an angiogenic response in the host vasculature. When evaluated in a mouse hind-limb ischemia model, the nanofibers increased tissue perfusion, functional recovery, limb salvage, and treadmill endurance compared to controls, which included the VEGF-mimetic peptide alone. Immunohistological evidence also demonstrated an increase in the density of microcirculation in the ischemic hind limb, suggesting the mechanism of efficacy of this promising potential therapy is linked to the enhanced microcirculatory angiogenesis that results from treatment with these polyvalent VEGF-mimetic nanofibers.

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Section: Discussionmentioning

confidence: 99%

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Webber

Tongers

Newcomb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

295

268

View full text Add to dashboard Cite

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“…At more infrequent administration, the erythropoietic activity of darbepoetin alfa observed far exceeded that predicted by the standard assay. We therefore concluded that units of erythropoietic activity were not suitable for determining darbepoetin alfa performance, or indeed any other erythropoietic protein engineered to outperform the endogenous protein or its recombinant counterpart [13, 14, 15, 16, 17]. Moreover, given that different doses of Epoetin alfa and darbepoetin alfa are required at different dosing intervals, these proteins cannot be regarded as biologically equivalent across the whole range of their activity.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Epoetin Alfa and Darbepoetin Alfa Biological Activity under Different Administration Schedules in Normal Mice

Sasu

Hartley²,

Schultz³

et al. 2005

Acta Haematol

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The unit of erythropoietic activity has long been the standard by which erythropoietic agents are judged, but the development of long-acting agents such as darbepoetin alfa has highlighted the shortcomings of this approach. To this point, we compared the in vivo activity of Epoetin alfa and darbepoetin alfa per microgram of protein core. Using the established mass-to-unit conversion for Epoetin alfa (1 µg ≅ 200 U), we then calculated darbepoetin alfa activity in units. Activity varied with treatment regimen (1 µg darbepoetin alfa ≅ 800 U for 3 times weekly dosing to 8,000 U for a single injection). This analysis reveals the inadequacy of evaluating darbepoetin alfa activity in terms of standard erythropoietic units. We therefore propose that for molecules with heightened biological activity, a more legitimate basis for comparison is the protein mass.

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“…Both hGH and EPO initiate downstream effects by binding two monomers of their receptors to form a trimeric complex~Wells & de Vos, 1993;Matthews et al, 1996!. Due to the availability of structural and mutational data for hGH and the hGHr, we chose to focus on this complex rather than on EPO or other cytokine0cytokine receptor systems. Monumental efforts have been made to design EPO agonists andantagonists~Wrighton et al, 1996, 1997;Johnson et al, 1997Johnson et al, , 1998!. Peptide EPO agonists were discovered~Wrighton et al, 1996!, and a small molecule agonist was found to activate the granulocyte-colony stimulating factor~Tian et al, 1998!, but small-molecule or peptide hGH agonists have not been reported.…”

mentioning

confidence: 99%

Macromolecular docking of a three‐body system: The recognition of human growth hormone by its receptor

1999

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Human growth hormone~hGH! binds to its receptor~hGHr! in a three-body interaction: one molecule of the hormone and two identical monomers of the receptor form a trimer. Curiously, the hormone-receptor interactions in the trimer are not equivalent and the formation of the complex occurs in a specific kinetic order~Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR, Wells JA, 1991, Science 254:821-825!. In this paper, we model the recognition of hGH to the hGHr using shape complementarity of the three-dimensional structures and macromolecular docking to explore possible binding modes between the receptor and hormone. The method, reported previously~Hendrix DK, Kuntz ID, 1998, Pacific symposium on biocomputing 1998, pp 1234-1244!, is based upon matching complementaryshaped strategic sites on the molecular surface. We modify the procedure to examine three-body systems. We find that the order of binding seen experimentally is also essential to our model. We explore the use of mutational data available for hGH to guide our model. In addition to docking hGH to the hGHr, we further test our methodology by successfully reproducing 16 macromolecular complexes from X-ray crystal structures, including enzyme-inhibitor, antibody-antigen, protein dimer, and protein-DNA complexes.

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Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

Cited by 53 publications

References 23 publications

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair

Comparison of Epoetin Alfa and Darbepoetin Alfa Biological Activity under Different Administration Schedules in Normal Mice

Macromolecular docking of a three‐body system: The recognition of human growth hormone by its receptor

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