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WO1997049729A1 - Polypeptides imitant l'activite de l'erythropoietine de l'homme - Google Patents

Polypeptides imitant l'activite de l'erythropoietine de l'homme Download PDF

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Publication number
WO1997049729A1
WO1997049729A1 PCT/EP1997/003228 EP9703228W WO9749729A1 WO 1997049729 A1 WO1997049729 A1 WO 1997049729A1 EP 9703228 W EP9703228 W EP 9703228W WO 9749729 A1 WO9749729 A1 WO 9749729A1
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WO
WIPO (PCT)
Prior art keywords
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ala
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Prior art date
Application number
PCT/EP1997/003228
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English (en)
Inventor
Dejan Markovic
Veljiko Veljkovic
Radmila Metlas
Original Assignee
Diapharm Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Diapharm Limited filed Critical Diapharm Limited
Priority to AU34353/97A priority Critical patent/AU3435397A/en
Priority to EP97930375A priority patent/EP0928292A1/fr
Priority to JP50230598A priority patent/JP2001510446A/ja
Publication of WO1997049729A1 publication Critical patent/WO1997049729A1/fr
Priority to NO985993A priority patent/NO985993L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/505—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention refers to polypeptides having a sequence obtained by the informational spectra method and the ability of stimulating the production of reticulocytes and red blood cells from bone marrow cells as well as hemoglobin synthesis and iron uptake.
  • EPO Human erythropoietin
  • erythropoiesis is a glycoprotem having a molecular weight of about 34-38 kd, the primary structure of which is shown in Figure 1.
  • EPO is presently obtained by recombmant DNA techniques using eukaryotic cells which can glycosylate the expression product.
  • polypeptides having in the informational spectrum obtained by Fourier transformation according to the informational analysis method substantially the same frequencies of natural erythropoietin, have substantially the same activity of human erythropoietin.
  • EIIP electron-ion interaction potential
  • the protein sequences are transformed into signals by assignment of numerical values to each ammo acid. These values correspond to EIIP [Veljkovic V. and Slavic I., Phys. Rev. Lett. , 29, 105 (1972); Veljkovic V. Phys Lett. , 45A, 41 (1973)].
  • the signal obtained is than decomposed in periodical function by Fourier transformation. The result is a series of frequencies and their amplitudes.
  • the obtained frequencies correspond to the distribution of structural motifs with defined physico-chemical characteristics responsible for biological function of protein.
  • the technique allows detection of code/frequency pairs which are specific for their common biological properties.
  • the method is insensitive to the location of the motifs and, thus, does not require previous alignment of the sequence.
  • the ISM was successfully applied m structure/function analysis and de novo design of peptides [Cosic I. and Nesis D. ,
  • An object of the invention is provided by EPO muteins having an homology degree with natural erythropoietin lower than 60% or polypeptides having from 20 to 100, preferably from 15 to 70 amino acids, characterized by informational spectrum having substantially the same frequencies as found in the informational spectrum of natural erythropoietin.
  • the muteins or polypeptides according to the invention may be designed so as to include appropriate 0- or N-glycosilation sites even though it has been surprisingly found that glycosilation is not always necessary for the biological activity.
  • the muteins or polypeptides of the invention are characterized by the frequency component 0.312 ⁇ 0.004 m the informational spectrum and at least one of the following frequency components:
  • the peptide may be cyclised or dimerised.
  • These peptides are able to bind to the erythropoietin receptor and show in the IS the frequency component 0.312 and the corresponding amplitude A >. 0.11.
  • the invention also refers to polynucleotide sequences coding for said muteins or polypeptides, to expression vectors comprising said polynucleotide sequences and to hosts transformed or transfected by said vectors, as well as to nucleotide sequences which hybridize to the above mentioned coding sequences.
  • polypeptides sequence of the invention are determined by a procedure involving the following steps: 1. determination of the consensus characteristic frequencies for the EPO molecules; 2. derivation of a new numerical sequence of the desired length having the same characteristic frequencies using inverse Fourier transformation; 3 determination of the ammo acid corresponding to each element of this new numerical sequence from values of EIIP (see Table 1):
  • polypeptides may be obtained by conventional methods of peptide synthesis or by known recombmant DNA techniques.
  • polypeptides or muteins of the invention may be administered to humans or animals in form of suitable pharmaceutical compositions, usually but not exclusively to be administered parenterally.
  • Said compositions will contain from 1 to about 100 mg of rnutein or polypeptide for the treatment of the same pathological conditions presently treated with human or recombmant EPO.
  • the following examples further illustrate the invention.
  • each constitutive element (ammo acid) in analyzed sequence is represented by corresponding EIIP value.
  • EIIP the following expression derived from the "general model pseudopotential" [Veljkovic V. and Slavic I., Phys. Rev. Lett., 21 , 105 (1972); Veljkovic V., Phys. Lett., 45A. 41 (1973)] was used:
  • the numerical centre determined in this way is fmite-lenght deterministic discrete signal containing information corresponding to selective long-distance interaction among biological macromolecules.
  • DFT discrete Fourier transformation
  • x(m) is the m-th of a given numerical series
  • X(n) are coefficients of DFT.
  • the coefficients are describing the amplitude, phase, and frequency of sinusoids from which original signal consists.
  • the analysis procedure comprises the following steps:
  • each ammo acid sequences was converted to the numerical sequence by representing each ammo acid with the corresponding value of the EIIP; 2. this numerical sequence was converted into a numerical spectrum using fast Fourier transform (hereinafter FFT); 3 spectra were mutually compared using cross-spectral analysis with the aim to extract common frequency components.
  • FFT fast Fourier transform
  • Table 3 show that the main part of information corresponding to human EPO-EPOR interaction is determined by the frequency component 0.311. It is also important to note that, taking into account accuracy of ⁇ 0.004 in the determination of frequency values, 8 of 10 characteristic frequencies from the EPO CIS (Table 2) are also contained within the first 15 characteristic ' frequencies in the human EPO- EPOR cross-spectrum (Table 3).
  • Example 4 Application of the technique in example 1 to design of EPO muteins
  • EPO muteins introducing a large number of amino acid substitutions in human EPO.
  • the main condition that must be satisfied in the design of these muteins is the conservation of IS of human EPO.
  • Figure 2a the primary structure of mutein-1 generated by substitution of 99 (56.6%) amino acids in human EPO is given (Sequence Id n. 1).
  • the IS of this mutein is given in Table 4 and Figure 4a. As can be seen, this IS contains all 10 characteristic EPO frequencies from Table 2, as well as other frequency components corresponding to first 15 amplitudes in IS of the human EPO.
  • NAME MARKOVIC Dejan
  • B STREET: Via Andrea Verga, 5

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne des polypeptides ou des mutéines d'érythropoïétine, caractérisées par une séquence d'acides aminés différente de celle de l'érythropoïétine de l'homme. En outre, dans le spectre d'informations obtenues par transformée de Fourier, selon le procédé d'analyses informatives, ils présentent sensiblement les mêmes fréquences que l'érythropoïétine de l'homme.
PCT/EP1997/003228 1996-06-25 1997-06-20 Polypeptides imitant l'activite de l'erythropoietine de l'homme WO1997049729A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU34353/97A AU3435397A (en) 1996-06-25 1997-06-20 Polypeptides mimicking the activity of human erythropoietin
EP97930375A EP0928292A1 (fr) 1996-06-25 1997-06-20 Polypeptides imitant l'activite de l'erythropoietine de l'homme
JP50230598A JP2001510446A (ja) 1997-06-20 1997-06-20 ヒトエリスロポエチン活性を模するポリペプチド
NO985993A NO985993L (no) 1996-06-25 1998-12-18 Polypeptider som etteraper aktiviteten til humant erytropoietin

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9613289A GB2318352A (en) 1996-06-25 1996-06-25 Polypeptides mimicking the activity of human erythropoietin
GB9613289.9 1996-06-25

Publications (1)

Publication Number Publication Date
WO1997049729A1 true WO1997049729A1 (fr) 1997-12-31

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/003228 WO1997049729A1 (fr) 1996-06-25 1997-06-20 Polypeptides imitant l'activite de l'erythropoietine de l'homme

Country Status (6)

Country Link
EP (1) EP0928292A1 (fr)
AU (1) AU3435397A (fr)
CA (1) CA2258871A1 (fr)
GB (1) GB2318352A (fr)
NO (1) NO985993L (fr)
WO (1) WO1997049729A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6987006B2 (en) 1992-01-31 2006-01-17 Aventis Behring L.L.C. Erythropoietin and albumin fusion protein, nucleic acids, and methods thereof
US7141547B2 (en) 2001-12-21 2006-11-28 Human Genome Sciences, Inc. Albumin fusion proteins comprising GLP-1 polypeptides
US7507414B2 (en) 2000-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
US7521424B2 (en) 2003-01-22 2009-04-21 Human Genome Sciences, Inc. Albumin fusion proteins

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112646023B (zh) * 2021-01-21 2022-05-31 浙江辉肽生命健康科技有限公司 具有氨基酸结构vnvvptfgkkkgp的生物活性肽及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017108A2 (fr) * 1992-02-19 1993-09-02 Centre National De La Recherche Scientifique (C.N.R.S.) Peptides analogues de l'image interne d'une proteine virale
WO1994024160A2 (fr) * 1993-04-21 1994-10-27 Brigham And Women's Hospital Erythropoïetines-muteines a activite renforcee

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ210501A (en) * 1983-12-13 1991-08-27 Kirin Amgen Inc Erythropoietin produced by procaryotic or eucaryotic expression of an exogenous dna sequence
US4835260A (en) * 1987-03-20 1989-05-30 Genetics Institute, Inc. Erythropoietin composition

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993017108A2 (fr) * 1992-02-19 1993-09-02 Centre National De La Recherche Scientifique (C.N.R.S.) Peptides analogues de l'image interne d'une proteine virale
WO1994024160A2 (fr) * 1993-04-21 1994-10-27 Brigham And Women's Hospital Erythropoïetines-muteines a activite renforcee

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COSIC I: "MACROMOLECULAR BIOACTIVITY: IS IT RESONANT INTERACTION BETWEEN MACROMOLECULES? - THEORY AND APPLICATIONS", IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, vol. 41, no. 12, 1 December 1994 (1994-12-01), pages 1101 - 1114, XP000556764 *
VELJKOVIC ET AL.: "It is possible to analise DNA and protein sequences by the method of digital signal processing ?", IEEE TRANSACTION ON BIOMEDICAL ENGINEERING, vol. 32, no. 5, 1985, pages 337 - 341, XP002042233 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7410779B2 (en) 1992-01-31 2008-08-12 Novozymes Biopharma Uk Limited Fusion polypeptides of human serum albumin and a therapeutically active polypeptide
US6989365B2 (en) 1992-01-31 2006-01-24 Aventis Behring L.L.C. Methods of treatment with erythropoietin and albumin fusion protein
US7056701B2 (en) 1992-01-31 2006-06-06 Aventis Behring L.L.C. Hormone and albumin fusion protein
US6987006B2 (en) 1992-01-31 2006-01-17 Aventis Behring L.L.C. Erythropoietin and albumin fusion protein, nucleic acids, and methods thereof
US7507414B2 (en) 2000-04-12 2009-03-24 Human Genome Sciences, Inc. Albumin fusion proteins
US7592010B2 (en) 2001-12-21 2009-09-22 Human Genome Sciences, Inc. Albumin fusion proteins
US7238667B2 (en) 2001-12-21 2007-07-03 Human Genome Sciences, Inc. Albumin fusion proteins
US7141547B2 (en) 2001-12-21 2006-11-28 Human Genome Sciences, Inc. Albumin fusion proteins comprising GLP-1 polypeptides
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins
US8071539B2 (en) 2001-12-21 2011-12-06 Human Genome Sciences, Inc. Albumin fusion proteins
US8252739B2 (en) 2001-12-21 2012-08-28 Human Genome Sciences, Inc. Albumin fusion proteins
US8513189B2 (en) 2001-12-21 2013-08-20 Human Genome Sciences, Inc. Albumin fusion proteins
US8993517B2 (en) 2001-12-21 2015-03-31 Human Genome Sciences, Inc. Albumin fusion proteins
US9221896B2 (en) 2001-12-21 2015-12-29 Human Genome Sciences, Inc. Albumin fusion proteins
US9296809B2 (en) 2001-12-21 2016-03-29 Human Genome Sciences, Inc. Albumin fusion proteins
US7521424B2 (en) 2003-01-22 2009-04-21 Human Genome Sciences, Inc. Albumin fusion proteins

Also Published As

Publication number Publication date
NO985993D0 (no) 1998-12-18
CA2258871A1 (fr) 1997-12-31
GB9613289D0 (en) 1996-08-28
GB2318352A (en) 1998-04-22
NO985993L (no) 1999-02-24
EP0928292A1 (fr) 1999-07-14
AU3435397A (en) 1998-01-14

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