United States Patent 7,557,182 [2009]{Molecules for transporting a compound across the blood-brain barrier}(IR91)

United States Patent 7,557,182 [2009]{Molecules for transporting a compound across the blood-brain barrier}(IR91)

FIELD OF THE INVENTION

The present invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptide, conjugates and pharmaceutical compositions comprising the polypeptides of the present invention and their use for transporting a compound or drug across the blood-brain barrier of an individual and in the treatment and diagnosis of neurological diseases.

BACKGROUND OF THE INVENTION

In the development of a new therapy for brain pathologies, the blood-brain barrier (BBB) is considered as a major obstacle for the potential use of drugs for treating disorders of the central nervous system (CNS). The global market for CNS drugs was $33 billion in 1998, which was roughly half that of global market for cardiovascular drugs, even though in the United States, nearly twice as many people suffer from CNS disorders as from cardiovascular diseases. The reason for this lopsidedness is that more than 98% of all potential CNS drugs do not cross the blood-brain barrier. In addition, more than 99% of worldwide CNS drug development is devoted solely to CNS drug discovery, and less than 1% is directed to CNS drug delivery. This ratio could explain why no efficient treatment is currently available for the major neurological diseases such as brain tumors, Alzheimer's and stroke.

The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). The BBB is considered to be the major route for the uptake of serum ligands since its surface area is approximately 5000-fold greater than that of BCSFB. The brain endothelium (內皮), which constitutes the BBB, represents the major obstacle for the use of potential drugs against many disorders of the CNS. As a general rule, only lipophilic molecules smaller than about 500 Daltons may pass across the BBB, i.e., from blood to brain. However, the size of many drugs that show promising results in animal studies for treating CNS disorders is considerably bigger. Thus, peptide and protein therapeutics are generally excluded from transport from blood to brain, owing to the negligible permeability of the brain capillary endothelial wall to these drugs. Brain capillary endothelial cells (BCECs) are closely sealed by tight junctions, possess few fenestrae and few endocytic vesicles as compared to capillaries of other organs. BCECs are surrounded by extracellular matrix, astrocytes, pericytes and microglial cells. The close association of endothelial cells with the astrocyte foot processes and the basement membrane of capillaries are important for the development and maintenance of the BBB properties that permit tight control of blood-brain exchange.

International publication WO2004/060403 discloses an invention made by the inventors relating to molecules for transporting a drug across the blood brain barrier. Otherwise, to date, there is no efficient drug delivery approach available for the brain. Methods under investigation for peptide and protein drug delivery to the brain may be divided in three principal strategies. Firstly, invasive procedures include the direct intraventricular administration of drugs by means of surgery, and the temporary disruption of the BBB via intracarotid infusion of hyperosmolar solutions. Secondly, the pharmacologically-based strategy consists in facilitating the passage through the BBB by increasing the lipid solubility of peptides or proteins. Thirdly, physiologic-based strategies exploit the various carrier mechanisms at the BBB, which have been characterized in the recent years. In this approach, drugs are attached to a protein vector that performs like receptors-targeted delivery vehicle on the BBB. This approach is highly specific and presents high efficacy with an extreme flexibility for clinical indications with unlimited targets. The latter approach has been, and is still, investigated by the inventors, who came up with the molecules described in the afore-mentioned publication and those of the present invention.

U.S. Pat. No. 5,807,980 describes Bovine Pancreatic Trypsin Inhibitor (aprotinin)-derived inhibitors as well as a method for their preparation and therapeutic use. These peptides are used for the treatment of a condition characterized by an abnormal appearance or amount of tissue factor and/or factor Villa such as abnormal thrombosis.

U.S. Pat. No. 5,780,265 describes serine protease inhibitors that are capable of inhibiting plasma kallikrein.

U.S. Pat. No. 5,118,668 describes Bovine Pancreatic Trypsin Inhibitor variants.

It would be highly desirable to be provided with improved molecules that can act as carriers or vectors for transporting a compound or drug across the BBB of an individual.

Choroid plexus protects cerebrospinal fluid against toxic metals [1991](IR91); The choroid plexus is the principal site of formation of the cerebrospinal fluid (CSF) which bathes the brain.

 

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Choroid plexus protects cerebrospinal fluid against toxic metals

http://www.fasebj.org/content/5/8/2188.abstract
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The FASEB Journal, Vol 5, 2188-2193, Copyright © 1991 by The Federation of American Societies for Experimental Biology

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RESEARCH COMMUNICATIONS

Choroid plexus protects cerebrospinal fluid against toxic metals
W Zheng, DF Perry, DL Nelson and HV Aposhian
Department of Pharmacology and Toxicology, University of Arizona, Tucson 86721.

Although heavy metal ions are known to be toxic to the central nervous system (CNS), the mechanisms by which the CNS may protect itself from initial challenges of such toxic ions is unknown. The choroid plexus is the principal site of formation of the cerebrospinal fluid (CSF) which bathes the brain. We have determined in rats and rabbits that after intraperitoneal administration of lead, cadmium, mercury, and arsenic compounds, these toxic metal ions accumulated in the lateral choroid plexus at concentrations of Pb, Hg, and As that were 70-, 95-, and 40- fold higher, respectively, than those found in the CSF. Cd was not detected in the CSF. In addition, concentrations of these heavy metal ions were found to be many fold greater in the choroid plexus than in the brain or blood. The accumulation of Pb in the choroid plexus was dose-dependent and time-related. When the choroid plexus was preincubated, in vitro, with ouabain (1.5 mM), the uptake of Cd from the CSF side of the choroid plexus was inhibited 57%. Cadmium metallothionein was not found in the choroid plexus. Whereas the concentration of reduced glutathione in the choroid plexus was less than that in the brain cortex, the concentration of cystine was fourfold greater. The lateral choroid plexus sequesters (使隔絕; 隔離) Pb, Cd, As, and Hg. It appears to be one of the important mechanisms that protects the CSF and the brain from the fluxes of toxic heavy metals in the blood.

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Normal alveolar epithelial lining fluid contains high levels of glutathione [1987](IR92)

Normal alveolar epithelial lining fluid contains high levels of glutathione [1987](IR92)

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(Memo Item created on November 15, 2010 11:01 AM)
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Normal alveolar epithelial lining fluid contains high levels of glutathione

http://jap.physiology.org/cgi/content/short/63/1/152
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J Appl Physiol 63: 152-157, 1987; 8750-7587/87 $5.00

Journal of Applied Physiology, Vol 63, Issue 1 152-157, Copyright © 1987 by American Physiological Society

ARTICLES

Normal alveolar epithelial lining fluid contains high levels of glutathione

A. M. Cantin, S. L. North, R. C. Hubbard and R. G. Crystal

The epithelial cells on the alveolar surface of the human lower respiratory tract are vulnerable to toxic oxidants derived from inhaled pollutants or inflammatory cells. Although these lung cells have intracellular antioxidants, these defenses may be insufficient to protect the epithelial surface against oxidants present at the alveolar surface. This study demonstrates that the epithelial lining fluid (ELF) of the lower respiratory tract contains large amounts of the sulfhydryl-containing antioxidant glutathione (GSH). The total glutathione (the reduced form GSH and the disulfide GSSG) concentration of normal ELF was 140-fold higher than that in plasma of the same individuals, and 96% of the glutathione in ELF was in the reduced form. Compared with nonsmokers, cigarette smokers had 80% higher levels of ELF total glutathione, 98% of which was in the reduced form. Studies of cultured lung epithelial cells and fibroblasts demonstrated that these concentrations of reduced glutathione were sufficient to protect these cells against the burden of H2O2 in the range released by alveolar macrophages removed from the lower respiratory tract of nonsmokers and smokers, respectively, suggesting that the glutathione present in the alveolar ELF of normal individuals likely contributes to the protective screen against oxidants in the extracellular milieu of the lower respiratory tract.

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Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen
Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L336 - L345. [Abstract] [Full Text] [PDF] J. Kloek, I. van Ark, N. Bloksma, F. De Clerck, F. P. Nijkamp, and G. Folkerts
Glutathione and other low-molecular-weight thiols relax guinea pig trachea ex vivo: interactions with nitric oxide?
Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L403 - L408. [Abstract] [Full Text] [PDF] H. J. Kim, X. Liu, H. Wang, T. Kohyama, T. Kobayashi, F.-Q. Wen, D. J. Romberger, S. Abe, W. MacNee, I. Rahman, et al.
Glutathione prevents inhibition of fibroblast-mediated collagen gel contraction by cigarette smoke
Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L409 - L417. [Abstract] [Full Text] [PDF] S. W. Griffiths, J. King, and C. L. Cooney
The Reactivity and Oxidation Pathway of Cysteine 232 in Recombinant Human alpha 1-Antitrypsin
J. Biol. Chem., July 5, 2002; 277(28): 25486 - 25492. [Abstract] [Full Text] [PDF] H. Jardine, W. MacNee, K. Donaldson, and I. Rahman
Molecular Mechanism of Transforming Growth Factor (TGF)-beta 1-induced Glutathione Depletion in Alveolar Epithelial Cells. INVOLVEMENT OF AP-1/ARE AND Fra-1
J. Biol. Chem., June 7, 2002; 277(24): 21158 - 21166. [Abstract] [Full Text] [PDF] B. Gaston and J. F. Hunt
How Acidopneic Is My Patient? A New Question in the Pulmonary Laboratory
Am. J. Respir. Crit. Care Med., May 15, 2002; 165(10): 1349 - 1350. [Full Text] [PDF] S. Hammerschmidt, N. Buchler, and H. Wahn
Tissue Lipid Peroxidation and Reduced Glutathione Depletion in Hypochlorite-Induced Lung Injury
Chest, February 1, 2002; 121(2): 573 - 581. [Abstract] [Full Text] [PDF] V L Kinnula, S Lehtonen, R Kaarteenaho-Wiik, E Lakari, P Paakko, S W Kang, S G Rhee, and Y Soini
Cell specific expression of peroxiredoxins in human lung and pulmonary sarcoidosis
Thorax, February 1, 2002; 57(2): 157 - 164. [Abstract] [Full Text] [PDF] G. Sun, K. Crissman, J. Norwood, J. Richards, R. Slade, and G. E. Hatch
Oxidative interactions of synthetic lung epithelial lining fluid with metal-containing particulate matter
Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L807 - L815. [Abstract] [Full Text] [PDF] S. Yang, V. A. Porter, D. N. Cornfield, C. Milla, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad
Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation
Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L922 - L930. [Abstract] [Full Text] [PDF] J. H. Roum, A. S. Aledia, L. A. Carungcong, K.-J. Kim, and Z. Borok
Extracellular glutathione inhibits oxygen-induced permeability changes in alveolar epithelial monolayers
J Appl Physiol, August 1, 2001; 91(2): 748 - 754. [Abstract] [Full Text] [PDF] E. Cavarra, M. Lucattelli, F. Gambelli, B. Bartalesi, S. Fineschi, A. Szarka, F. Giannerini, P. A. Martorana, and G. Lungarella
Human SLPI inactivation after cigarette smoke exposure in a new in vivo model of pulmonary oxidative stress
Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L412 - L417. [Abstract] [Full Text] [PDF] L. Gao, J. R. Broughman, T. Iwamoto, J. M. Tomich, C. J. Venglarik, and H. J. Forman
Synthetic chloride channel restores glutathione secretion in cystic fibrosis airway epithelia
Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L24 - L30. [Abstract] [Full Text] [PDF] L. W. Velsor, A. van Heeckeren, and B. J. Day
Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice
Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L31 - L38. [Abstract] [Full Text] [PDF] B. Nemery, A. Bast, J. Behr, P.J.A. Borm, S.J. Bourke, Ph. Camus, P. De Vuyst, H.M. Jansen, V.L. Kinnula, D. Lison, et al.
Interstitial lung disease induced by exogenous agents: factors governing susceptibility
Eur. Respir. J., July 1, 2001; 18(32_suppl): 30S - 42s. [Abstract] [Full Text] [PDF] N Dauletbaev, J Rickmann, K Viel, R Buhl, T-O-F Wagner, and J Bargon
Glutathione in induced sputum of healthy individuals and patients with asthma
Thorax, January 1, 2001; 56(1): 13 - 18. [Abstract] [Full Text] X. Jiang, D. H. Ingbar, and S. M. O'Grady
Selectivity properties of a Na-dependent amino acid cotransport system in adult alveolar epithelial cells
Am J Physiol Lung Cell Mol Physiol, November 1, 2000; 279(5): L911 - L915. [Abstract] [Full Text] [PDF] C. Rusznak, P. R. Mills, J. L. Devalia, R. J. Sapsford, R. J. Davies, and S. Lozewicz
Effect of Cigarette Smoke on the Permeability and IL-1beta and sICAM-1 Release from Cultured Human Bronchial Epithelial Cells of Never-Smokers, Smokers, and Patients with Chronic Obstructive Pulmonary Disease
Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 530 - 536. [Abstract] [Full Text] N. E. AVISSAR, C. K. REED, C. COX, M. W. FRAMPTON, and J. N. FINKELSTEIN
Ozone, But Not Nitrogen Dioxide, Exposure Decreases Glutathione Peroxidases in Epithelial Lining Fluid of Human Lung
Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1342 - 1347. [Abstract] [Full Text] [PDF] A. M. CANTIN, B. PAQUETTE, M. RICHTER, and P. LARIVEE
Albumin-mediated Regulation of Cellular Glutathione and Nuclear Factor Kappa B Activation
Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): 1539 - 1546. [Abstract] [Full Text] [PDF] K. Fang, R. Johns, T. Macdonald, M. Kinter, and B. Gaston
S-nitrosoglutathione breakdown prevents airway smooth muscle relaxation in the guinea pig
Am J Physiol Lung Cell Mol Physiol, October 1, 2000; 279(4): L716 - L721. [Abstract] [Full Text] [PDF] R. M. Balansky, F. D'Agostini, A. Izzotti, and S. De Flora
Less than additive interaction between cigarette smoke and chromium(VI) in inducing clastogenic damage in rodents
Carcinogenesis, September 1, 2000; 21(9): 1677 - 1682. [Abstract] [Full Text] [PDF] J. BEHR, B. DEGENKOLB, T. BEINERT, F. KROMBACH, and C. VOGELMEIER
Pulmonary Glutathione Levels in Acute Episodes of Farmer's Lung
Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 1968 - 1971. [Abstract] [Full Text] W. MacNee
Oxidants/Antioxidants and COPD
Chest, May 1, 2000; 117 (2009): 303S - 317S. [Abstract] [Full Text] [PDF] S. De Flora
Threshold mechanisms and site specificity in chromium(VI) carcinogenesis
Carcinogenesis, April 1, 2000; 21(4): 533 - 541. [Abstract] [Full Text] [PDF] S. O Shaheen, J. A C Sterne, C. E Songhurst, and P. G J Burney
Frequent paracetamol use and asthma in adults
Thorax, April 1, 2000; 55(4): 266 - 270. [Abstract] [Full Text] B. Lothian, V. Grey, R. J. Kimoff, and L. C. Lands
Treatment of Obstructive Airway Disease With a Cysteine Donor Protein Supplement: A Case Report
Chest, March 1, 2000; 117(3): 914 - 916. [Abstract] [Full Text] [PDF] M. MOSS, D. M. GUIDOT, M. WONG-LAMBERTINA, T. TEN HOOR, R. L. PEREZ, and L. A. S. BROWN
The Effects of Chronic Alcohol Abuse on Pulmonary Glutathione Homeostasis
Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): 414 - 419. [Abstract] [Full Text]
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The structure of ATP synthase, the universal protein that manufactures ATP; Photo courtesy of Professor George Oster; Department of Molecular and Cell Biology, University of California, Berkeley [2000](IR92)

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The structure of ATP synthase, the universal protein that manufactures ATP; Photo courtesy of Professor George Oster; Department of Molecular and Cell Biology, University of California, Berkeley [2000](IR92)

http://mcb.berkeley.edu/gallery2/main.php?g2_itemId=99
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The structure of ATP synthase, the universal protein that manufactures ATP; Photo courtesy of Professor George Oster; Department of Molecular and Cell Biology, University of California, Berkeley [2000](IR92)

The structure of ATP synthase, the universal protein that manufactures ATP.

The structure of ATP synthase consists of two rotary motors, labeled F1 and Fo, that are connected by a flexible shaft. Under normal operation, the Fo motor uses the energy stored in a transmembrane ion gradient to drive the F1 motor in reverse so that ATP is synthesized from ADP and phosphate. In bacteria, anerobic conditions wipe out the ion gradient whereupon the F1 part becomes a motor, using the energy of ATP hydrolysis to turn the Fo part in reverse so that it functions as an ion pump.

Oster, G., and Wang, H. (2000). Reverse engineering a protein: The mechanochemistry of ATP synthase. Biochimica et Biophysica Acta 1458, 482-510.
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Microtubule-driven self-assembly (自我組裝的) of the Dam1 kinetochore ring. [2010-11-03](IR92)

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(Memo Item created on November 3, 2010 08:59 PM)
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Microtubule-driven self-assembly of the Dam1 kinetochore ring.
Microtubule-driven self-assembly (自我組裝的) of the Dam1 kinetochore ring. [2010-11-03](IR92)

http://mcb.berkeley.edu/gallery2/main.php?g2_itemId=172
Department of Molecular and Cell Biology, University of California, Berkeley
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Microtubule-driven self-assembly of the Dam1 kinetochore ring.

The yeast kinetochore complex Dam1 self-assembles around microtubules forming rings that can diffuse on the microtubule lattice and harvest the energy of microtubule disassembly to move processively towards the poles during anaphase.

(These studies are being carried out as a collaboration of three MCB faculty members: Georjana Barnes, David Drubin and Eva Nogales)

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hydrogen (H)(氫); carbon (C)(碳); nitrogen (N)(氮); oxygen (O)(氧); phosphorus (P)(磷); sulfur (S)(硫); selenium (Se)(硒)

2010-11-03

hydrogen (H)(【化】氫)

carbon (C)(【化】碳)

nitrogen (N)(【化】氮)

oxygen (O)(【化】氧)

phosphorus (P)(【化】磷)

sulfur (S)(【化】硫)

selenium (Se)(【化】硒)

Element (元素) – hydrogen (H)(【化】氫) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png
Element (元素) – carbon (C)(【化】碳) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png
Element (元素) – nitrogen (N)(【化】氮) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png
Element (元素) – oxygen (O)(【化】氧) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png
Element (元素) – sulfur (S)(【化】硫) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png
Element (元素) – selenium (Se)(【化】硒) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png

Element (元素) – phosphorus (P)(【化】磷) with electron configuration (電子組態) and electron orbital (電子軌域) [2010-11-02].png

Element (元素) – oxygen (O)(【化】氧) with 1s, 2s, 2p electron orbital (電子軌域) [2010-11-02] 01.png
Element (元素) – oxygen (O)(【化】氧) with 1s, 2s, 2p electron orbital (電子軌域) [2010-11-02] 02.png
Element (元素) – oxygen (O)(【化】氧) with 1s, 2s, 2p electron orbital (電子軌域) [2010-11-02] 03.png
Element (元素) – oxygen (O)(【化】氧) with 1s, 2s, 2p electron orbital (電子軌域) [2010-11-02] 04.png

Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 01.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 02.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 03.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 04.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 05.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 06.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 07.png
Element (元素) – selenium (Se)(【化】硒) with 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p electron orbital (電子軌域) [2010-11-02] 08.png

Scientific research activities of WeiJin Tang (湯偉晉 在進行的 科學性研究活動)

2010-11-03

http://ScientificResearchWJ.blogspot.com/

Scientific Research (科學研究)

Scientific research activities of WeiJin Tang (湯偉晉 在進行的 科學性研究活動)