WO1999041283A1

WO1999041283A1 - Pf4 fragments and pharmaceutical compositions containing same

Info

Publication number: WO1999041283A1
Application number: PCT/FR1999/000169
Authority: WO
Inventors: Monica Alemany; Jacques Caen; Paul Cohen; Zhong Chao Han; Mohamed Rholam
Original assignee: Institut Des Vaisseaux Et Du Sang
Priority date: 1998-02-16
Filing date: 1999-01-28
Publication date: 1999-08-19
Also published as: EP1058692A1; FR2774990A1; JP2002509079A; FR2774990B1

Abstract

The invention concerns as novel industrial products: (a) peptides corresponding to the formula (I): X01 X02 Ser X04 X05 X06 X07 X08 X09 X10 X11 X12 X13 X14 X15 Gln X17 X18 Ser X20 Asp Leu Gln X24 X25 where X01, X02, X04, X05, X06, X08, X09, X10, X11, X12, X13, X14, X15, X17, X18, X20, X24 and X25 are such as defined in the description, and (b) their non-toxic additive salts. Said novel products are useful in therapy.

Description

MODIFIED PF4 FRAGMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Field of the Invention The present invention relates, as new industrial products, to the peptides of formula I below. It also relates to the therapeutic use of these peptides, as well as the pharmaceutical compositions containing them. PRIOR ART To the knowledge of the Applicant, the peptides of formula I, according to the invention, are new and there is in the prior literature no analogous peptide product which, like said peptides of formula I, (a) active on hematopoietic cells (in particular at the level of inhibition of proliferation and at the level of cytoprotection), and (b) effective in the expansion of hematopoietic cells and / or spinal bleeding. Subject of the invention

According to a first aspect of the invention, it is recommended, eir as a new peptide compound, a product characterized in that it is chosen from the group consisting of: (a) the peptides corresponding to formula I:

X (H Xθ2 Ser Xθ4 Xθ5 Xθ6 θ7 Xθ8 Xθ9 - ^ 10 Xll ^ 12 - ^ 13 - ^ 14 Xl5 Gin X _l7 X _l8 Ser X ₂ o Asp Leu Gin X ₂₄ Y ₂ s (I)

[see SEQ. ID. No: 1 (when Y ₂₅ is Pro), SEQ. ID. No: 2 (when Y ₂₅ is Pro-X ₂ 6) and SEQ. ID. No: 3 (when Y ₂₅ is Pro-X ₂₆ -Tyr)] in which,

XQI is Pro, Gly or Ala, the preferred amino acid residues being Pro and Ala, XQ2 is any amino acid residue other than Cys and advantageously represents His or Glx, the preferred residue being His, X04 is Pro, Gly, Thr, Ala, Ile or Leu, the preferred amino acid residues being Pro, Ala and Leu, X05 is any amino acid residue other than Cys and advantageously represents Thr, Glx, Asx or Ala, the preferred residue being Thr, X ₀ 6 represents Ala, Val, Gin, Leu, Ile or Thr, the preferred amino acid residue being Ala, X07 is any amino acid residue other than Cys and advantageously represents Ala or Glx, X _Q 8 is any amino acid residue other than Cys and advantageously represents Ile, Leu or Val, X09 is any amino acid residue other than Cys and advantageously represents Ile, Leu or Val, the preferred residue being Ile, X _l O is any amino acid residue other than Cys and advantageously represents Ala or Val ,

X _\ l is any amino acid residue other than Cys and advantageously represents Lys, Ser or Thr, the preferred residue being Thr, X _j2 is any amino acid residue different from Cys and advantageously represents Leu or Ile, the preferred residue being Leu, X13 is any amino acid residue other than Cys and advantageously represents Lys or Ser, X _j 4 is any amino acid residue different from Cys and advantageously represents Asx or Glx, the preferred residue being Asn, X _l 5 is any amino acid residue different from Cys and advantageously represents Gly,

Xl7 is any amino acid residue other than Cys and advantageously represents Lys or Gin, X _j g is Leu, Ile, Val, Ala or Tyr, the preferred residue being Ile, X ₂ 0 is Leu, Ile or Val, the preferred residue being Leu, X ₂ 4 is any amino acid residue other than Cys and advantageously represents Ala, Asx, Glx or Ser, the preferred residues being Ala and Glu, Y ₂ 5 is a Pro, Pro-X ₂ 6 or Pro-X ₂ residue g-Tyr, the preferred residue being the monoamino acid residue Pro, X ₂ g is any amino acid residue other than Cys and advantageously represents Arg, Ile, Leu, Val, Met or Trp, the preferred residue being Leu; and, (b) their non-toxic acid addition salts.

The peptides of formula I according to the invention can be used as such or in the form of addition salts with a mineral or organic acid, in particular hydrochloric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid or paratoluenesulfonic acid.

According to a second aspect of the invention, the use of the products according to the invention is recommended, which is characterized in that use is made of a peptide compound chosen from the group consisting of (a) the peptides of formula I and (b) their non-toxic acid addition salts, for the preparation of a medicament:

(1) hematopoiesis inhibitor, intended for therapeutic use with respect to myeloproliferative syndromes; (2) cytoprotector, intended for use in therapy with respect to cytotoxic attacks; (3) stimulating the expansion of hematopoietic cells and / or spinal cord purge, intended for use in therapy with regard to spinal cord insufficiency or in the event of a spinal cord transplant; (4) having an inhibitory effect on the differentiation of hematopoietic cells allowing the expansion of the least differentiated hematopoietic cells during the ex vivo expansion protocols of hematopoietic cells;

(5) anti-angiogenesis, intended for therapeutic use with respect to pathological angiogenesis;

(6) virustatic, intended for therapeutic use with regard to viral affections; and or,

(7) anti-inflammatory, intended for therapeutic use against inflammations. The beneficial effects indicated in points 1-4 above manifest themselves specifically on normal cells (i.e. healthy) but are not observed on abnormal cells, in particular leukemic and cancer cells.

Finally, according to a third aspect of the invention, a therapeutic composition is recommended which is characterized in that it contains, in association with a physiologically acceptable excipient, at least (a) a peptide of formula I mentioned above, or (b) one of its non-toxic acid addition salts. Abbreviations

In the present description, a large number of abbreviations have been used for convenience. For conventional amino acid residues, use was made of (i) the one-letter code and (ii) the three-letter code, as recommended by IUPAC; in this perspective B (Asx) represents N (Asn) or D (Asp), on the one hand, and Z (Glx) represents Q (Gln) or E (Glu), on the other hand. The other abbreviations and acronyms used are as follows: ASA aplastic anemia serum (in English: "aplastic anemia serum)

BP bovine plasma citrate BSA bovine serum albumin

BFU-E unit forming erythroblast (in English: "burst-forming unit-erythroblast") CFU unit forming colony (in English: "colony-forming unit")

CFU-GM granulocyte / macrophage colony forming unit (in French: "colony-forming unit-granulocyte / macrophage")

CFU-MK megakaryocyte colony forming unit (in English: "colony-forming unit-megakaryocyte") CSF colony stimulating factor (in English: "colony-stimulating factor") FITC fluorescein isothiocyanate

5FU 5-fluorouracil, reference cytotoxic product

GM-CSF granulocyte / macrophage colony stimulating factor

: "granulocyte / macrophage colony-stimulating factor") HPLC high performance liquid chromatography 2ME 2-mercaptoethanol

MEM minimal essential medium

O.MEM MEM modified

MK megakaryocyte

PB S saline phosphate buffer TGF-βl transforming growth factor beta 1 (in English: "transforming growth factor βl"), one of the reference products inducing apoptosis IU international unit Detailed description of the invention

The biological and pharmacological properties of the compounds according to the invention are largely due to their ability to organize into one or more secondary structures (α helix, β sheets and β elbows) allowing them to adopt particular conformations. The concepts of α helix, β sheets and β elbows appear in the literature and are well known to those skilled in the art. See in particular S. MARQUSEE et al., Proc. Natl. Acad. Sci. USA, 1989; 86, pages 5286-5290, on the one hand, and C.R. MATTHEWS et al, Annu. Rev. Biochem., 1993; 62, pages 653-683, on the other hand.

For the peptides of formula I, the peptide segment (S) starting at X ₀₄ and ending towards X ₁₅ has the property of forming a stable α helix. The helicity of this segment S and of the peptide of formula I containing it is important or even essential for the manifestation of the biological and pharmacological properties of the products of the invention;

1) the maintenance and stability of the α helicity of said segment require, according to the depositor's experiments, the presence at the N ** - terminal end of X ₀₄ of residues 1 to 3 of the sequence X ₀₁ -X ₀₂ - Ser ₀₃ ; the partial or total deletion of said sequence upstream of X ₀₄ results in: (i) reducing the α helicity of the peptides of formula I calculated by means of a database (see V. MUNOZ et al., Nature : Struct. Biol., 1994; I, pages 399-409) and measured by circular and infrared dichroism in Fourier Transform,

(ii) invert the ratio R (α helix / β structures) measured by circular and infrared dichroism in Fourier Transform, and

(iii) significantly reduce the biological properties of the peptides resulting from said deletion compared to the peptides of formula I according to the invention;

2) according to the Applicant, the choice of the residues at positions 4 and 6 of the peptide of formula I, namely Xo ₄ and X ₀₆ , is important with regard to the helicity α and the ratio R; also to have a maximum α helicity percentage and to increase said ratio R, it is recommended according to the invention to use:

(i) to a residue X ₀₄ which is Pro and better Ala or Leu, and (ii) to a residue X ₀₆ which is advantageously Ala, Leu or Ile

; for example a residue X ₀₆ ⁼ Pro considerably reduces the percentage of α helix of the S segment and of the peptides containing said S segment, on the one hand, and reduces by a factor of 500 to 1000 the biological and pharmacological activities of said peptides resulting from the substitution X ₀₆ = Pro, on the other hand; and,

3) the peptides according to the invention have in their S segment a maximum α helicity located at the amino acid residues 7 to 11 (more mainly at the residue 9) of the sequence of formula I. For these peptides, this α helicity maximum is greater than or equal to 0.12 units. In addition to the S segment, the sequence of the amino acid residues from position 16 approximately to position 25 has an influence on the activities of the peptides of formula I according to the invention. Beyond position 25, the insertion of a few additional amino acid residues (in particular 1 to 5) practically does not modify said activities. Consequently (i) the C-terminal end of the peptides of formula I can be stopped at position Y ₂₅ = Pro (pentacosapeptide compounds), and (ii) the sequence can be continued until position 27 to introduce therein. fine a Tyr residue in order to have peptides suitable as biological reagents for diagnosis.

It is recommended, from an analytical point of view (notably in the field of diagnosis and that of pharmacological experimentation), to have at least one Tyr residue in the amino acid sequence of the peptides of formula I. The Tyr residue, which is in particular more easily detectable or labeling (by means of a radioisotope) than the other natural amino acid residues, can be located in one of the positions 2, 5, 7 to 15, 17, 24 or 27 in the peptide of formula I.

Experimentally it has been found that it is more analytically practical for Tyr to be the last amino acid residue of the C-terminus. In other words, the Tyr residue, if present, will preferably be located in position 27 in formula I. The peptides of formula I according to the invention can exhibit up to seven essential activities (1-7) divided into three functional classes (AC), namely that they are useful - class A (hematopoietic function)

(1) as inhibitors of hematopoiesis, and more specifically as inhibitors of hematopoietic proliferation (interesting effect with respect to myeloproliferative syndromes);

(2) as cytoprotective agents, and in particular in the anti-apoptotic cytoprotection of hematopoietic stem cells;

(3) as products having an inhibitory effect on the differentiation of hematopoietic cells; (4) as hematopoietic expanding agents and / or medullary bleeding;

- class B (angiogenic function)

(5) as anti-angiogenesis agents; and or,

- class C (anti-inflammatory function)

(6) as virustatic agents, in particular with regard to viruses and retroviruses with a lipid capsid;

(7) as anti-inflammatory agents.

The myeloproliferative syndromes mentioned above include in particular: (1 °) essential thrombocytemia, (2 °) polycythemia vera, (3 °) myelofibrosis and (4 °) chronic myeloid leukemia. By the term "hematopoietic blowing agent" is meant here a product which acts at the level of hematopoietic cells by promoting or stimulating the growth of stem cells such as those which are at the origin of granulocytes, platelets and erythrocytes .

Spinal bleeding often occurs after spinal cord expansion. It is necessary in the event of a bone marrow transplant.

The effect on cell differentiation results in a delay in the disappearance of very early differentiation markers (CD34) from more immature cells. This suggests that cells treated with the peptides of the invention remain in an undifferentiated or more immature state. In addition, it has been found that the peptides of formula I have a beneficial effect on the cell cycle by prolonging the S phase (which occurs during mitosis).

Furthermore, it has been found that heparinic substances do not inhibit the activity of the peptides according to the invention. The peptides of formula I can be prepared according to a method known per se by application of conventional chemical or biological reaction mechanisms, namely by peptide synthesis or by genetic engineering. In short, each compound of formula I according to the invention has, at its amino acid residues 7 to 11, (i) a maximum α helicity which is greater than or equal to 0.12, and (ii) a higher R ratio or equal to 2.

A number of examples according to the invention and results of pharmacological tests have been provided below. All of these elements are in no way limiting but are given by way of illustration. Examples 1-26

Representative examples of the invention have been given in Table I below. They were prepared by peptide synthesis according to the conventional solid phase technique and then purified by HPLC on a column. For convenience, the comparative examples CP 1 to CP 3 have been inserted in said table I. Tests 1. Inhibition of hematopoiesis

The study of hematopoiesis inhibition was undertaken on hematopoietic stem cells (CFU-MK, CFU-GM and BFU-E), in order to assess the possible inhibitory power of hematopoietic proliferation of the products according to l 'invention. 1.1 CFU-MK MK and their progenitor cells were studied using a plasma clot system. After sacrifice of mice [male Balb / C mice aged 6-8 weeks] by cervical dislocation, the bone marrow of the femurs is collected using 5 ml of αMEM. 2x10 ⁵ nucleated medullary cells are cultured (at least in triplicate) in petri dishes (0 = 35 mm) in a total volume of 1 ml of a mixture of BSA (1%), BP (10%), 2ME ( ÎO- ⁴ M), CaCl ₂ (0.34 mg), penicillin (15 IU), streptomycin (15 μg) and ASA (10%), ASA obtained from pig blood collected 5 days after total body irradiation of 8 Gy. The peptides to be tested are added exogenously just before the test of the plasma clot. Heparin (5 IU / box) is added after the clot has formed. Cultures are incubated at 37 ° C in a humid atmosphere containing C0 ₂ (5%). After 7 days of culture, the dishes are fixed using 1% paraformaldehyde and stained for determination, with acetylcholinesterase, of the number of colonies originating from CFU-MK, a colony of CFU-MK is defined as being a cluster of three or more cells. The number of MKs and their colonies, on the one hand, and the area of each MK, on the other hand, are counted by means of an automatic analyzer.

The results obtained on total marrow of mice (inhibition of megakaryocytopoiesis) are recorded in Table II below where the content of CFU-MK is expressed as a percentage relative to the control batch (control animals receiving none of the peptides to be tested) depending on the doses used. They show that the products of the invention inhibit the proliferation of CFU-MK, more effectively than the products of the comparative examples. 1.2 CFU-GM and BFU-E

Nuclear medullary cells (10 ⁵ cells / ml) are available in a semi-solid medium containing the following ingredients: methylcellulose (0.8%), ASA (10%), 2ME (ÎO- ⁴ M), murine recombinant SCF [ ie rmSCF] (10 ng / ml), rmGM-CSF (10 ng / ml). Three cultures are used per dose of each product to be tested. The cultures are incubated at 37 ° C. for 5 days under a humid atmosphere containing CO (5%). The colonies of BFU-E (> 3 clusters of 20 cells) and CFU-GM (> 50 cells) are then counted.

The results obtained (inhibition of granulocytes and macrophages) are recorded in Table III below where the content of CFU-GM and BFU-E is given as a percentage relative to the control batch, depending on the doses used. 1.3 Tests on CD34 ⁺ murine cells

Mouse bone marrow cells are incubated with anti-CD34 ⁺ rat monoclonal antibodies [antibody "RAM34" marketed by the company called PHARMINGEN] coupled to biotin for 0.5 h on ice. Washed twice with PBS-BSA and stained with streptavidin coupled to FITC (ie streptavidin-FITC, product sold by the company called CALTAG). The cells used as control are stained with rat immunoglobins IgG2a [clone "R35-95" from the company called PHARMINGEN] coupled with biotin and streptavidin-FITC. We collect the 10

Purified and viable murine CD34 ⁺ cells. These cells are placed in a tube containing AAS (10%) then counted and reanalyzed to check their purity. Then 24,000 cells / ml of CD34 ⁺ are cultured on a plasma clot system for the determination of CFU-MK as indicated above, and 16,000 cells / ml of CD34 ⁺ are in parallel cultured on medium containing methylcellulose for the determination of CFU-GM and BFU-E as indicated above.

The results obtained are reported in Table IV below. The CFU-MK, CFU-GM and BFU-E contents are expressed as a percentage relative to the control batches (1 batch for each stem cell) as a function of the concentrations used for the peptides tested. 2. Protection of cellular apoptosis

The anti-apoptotic cytoprotection of hematopoietic stem cells was studied on CD34 ⁺ cells from human peripheral blood. The results obtained, expressed as a percentage of apoptotic cells, observed (a) in the absence of product to be tested and (b) in the presence of product to be tested, show that the products of the invention provide better protection than the products of comparative examples. Sequence list In the sequence list which follows, (i) the products of formula I are represented by SEQ. ID. No: 1 to 3, as indicated above, (ii) the products of Examples 1 to 26 are represented by SEQ. ID. No: 4 to 29, and (iii) the comparison products CP1 to CP3 are represented by SEQ. ID. No: 30 to 32.

11

TABLE I

Product Structure

Ex 1 PHSPTAQLIA TLKNGQKISL DLQAP

Ex 2 PHSPTVQLIA TLKNGQKISL DLQAP

Ex 3 PYSPTAQLIA TLKNGQKISL DLQEP

Ex 4 PHSPQTELIV KLKNGQKISL DLQAP

Ex 5 PHSPTAQLIA TLKNGQKISV DLQAP

Ex 6 AHSPTAQLIA TLKNGQKISL DLQAP

Ex 7 AHSPTVQLIA TLKNGQQISL DLQAP

Ex 8 AYSPTAQLIA TLKNGQKISL DLQEP

Ex 9 AHSPQTELIV KLKNGQKISL DLQAP

Ex 10 AHSPTAQLIA TLKNGQKISV DLQAP

Ex 11 PHSATAQLIA TLKNGQKISL DLQAP

Ex 12 PHSATVQLIA TLKNGQKISL DLQAP

Ex 13 PYSATAQLIA TLKNGQKISL DLQEP

Ex 14 PHSAQTELIV KLKNGQKISL DLQAP

Ex 15 PHSATAQLIA TLKNGQKISV DLQAP

Ex 16 AHSATAQLIA TLKNGQKISL DLQAP

Ex 17 AHSATVQLIA TLKNGQQISL DLQAP

Ex 18 AYSATAQLIA TLKNGQKISL DLQEP

Ex 19 AHSAQTELIV KLKNGQKISL DLQAP

Ex 20 AHSATAQLIA TLKNGQKISV DLQAP

Ex 21 PHSPTAQLIA TLKNGQKISL DLQAPLY

Ex 22 PHSPTVQLIA TLKNGQKISL DLQAPLY

Ex 23 AHSATAQLIA TLKNGQKISL DLQAPLY

Ex 24 PHSPQTELIV KLKNGQKISL DLQAPRY

Ex 25 PHSPTAQLIA TLKNGQKISL DLQAPRY

Ex 26 PHSTAAQLIA TLKNGQKISL DLQAPLY

CP 1 PHCPTAQLIA TLKNGRKICL DLQAP

CP 2 PHSPTPQLIA TLKNGQKISL DLQAP

CP 3 PHSTAPQLIA TLKNGQKISL DLQAPLY 12

TABLE II Megakaryocytopoiesis (determination on total mouse marrow)

Product Dose (nM) CFU-MK (a)

(witness) 0 100%

0.22 71%

Exl 2.2 65%

22.0 62%

76.0 60%

0.22 69%

Ex 16 2.2 62%

22.0 60%

76.0 59%

0.22 72%

Ex 23 2.2 66%

22.0 62%

76.0 61%

0.22 69%

Ex 26 2.2 63%

22.0 59%

76.0 58%

0.22 90%

CP1 2.2 68%

22.0 63%

76.0 61%

0.22 95%

CP2 2.2 94%

22.0 93%

76.0 92%

0.22 95%

CP3 2.2 94%

22.0 93%

76.0 90%

Note:

(a) CFU-MK content in percentage compared to the control batch 13

TABLE III

Granulocytopoiesis and erythrocytopoiesis

(determination on culture of mouse marrow cells in methylcellulose)

Product Dose (nM) CFU-GM (b) BFU-E (c)

(witness) 0 100% 100%

0.22 59% 56%

Ex 16 2.2 57% 51%

22.0 56% 49%

76.0 56%

0.22 59% 56%

Ex 23 2.2 57% 51%

22.0 56% 49%

76.0 55%

0.22 61% 52 Υ

Ex 26 2.2 60% 51%

22.0 59% 50%

76.0 59%

0.22 75% 70%

CP1 2.2 72% 68%

22.0 68% 65%

76.0 67%

Notes:

(b) CFU-GM content in percentage compared to the control batch

(c) BFU-E content in percentage compared to the control batch

283

14

TABLE IV

Overall hematopoiesis (determination of murine CD34 ⁺ cells)

dose CFU-MK CFU-GM BFU-E

Product (nM) (a) (b) (c)

(witness) 0 100% 100% 100%

0.22 80% 79% 76%

Exl 2.2 62% 60% 62% 22.0 60% 59% 61% 76.0 57% 57% 59%

0.22 80% 78% 75% 2.2 62% 60% 62%

Ex 21 22.0 60% 58% 60% 76.0 57% 56% 58%

0.22 95% 97% 112%

CP1 2.2 74% 85% 82% 22.0 70% 70% 70% 76.0 64% 70% 69%

Notes

(a) CFU-MK content in percentage compared to the control batch

(b) CFU-GM content in percentage compared to the control batch

(c) BFU-E content in percentage compared to the control batch

Claims

15 REVENDICA TIONS

1. Peptide compound, characterized in that it is chosen from the group consisting of:

(a) the peptides corresponding to formula I:

Xθi Xθ2 Ser Xo ₄ θ5 ^ 06 X ₀ 7 Xθ8 Xθ9 XlO Xll X-.2 Xl3 Xl4 Xl5 Gin Xl7 X-.8 Ser X ₂₀ Asp Leu Gin X ₂₄ Y 5 (I)

in which,

X _Q I is Pro, Gly or Ala, the preferred amino acid residues being Pro and

Ala, Xθ2 is any amino acid residue other than Cys and advantageously represents His or Glx, the preferred residue being His,

X04 is Pro, Gly, Thr, Ala, Ile or Leu, the preferred amino acid residues being Pro, Ala and Leu, X05 is any amino acid residue other than Cys and advantageously represents Thr, Glx, Asx or Ala, the preferred residue being Thr , Xo6 represents Ala, Val, Gin, Leu, Ile or Thr, the preferred amino acid residue being Ala, X07 is any amino acid residue other than Cys and advantageously represents Ala or Glx, Xos is any amino acid residue different from Cys and advantageously represents Ile, Leu or Val,

X09 is any amino acid residue different from Cys and advantageously represents Ile, Leu or Val, the preferred residue being Ile, X10 is any amino acid residue different from Cys and advantageously represents Ala or Val, Xu is any amino acid residue different from Cys and advantageously represents Lys, Ser or Thr, the preferred residue being Thr, Xl2 is any amino acid residue other than Cys and advantageously represents Leu or Ile, the preferred residue being Leu, Xl3 is any amino acid residue other than Cys and advantageously represents Lys or Ser, 16

X _j 4 is any amino acid residue other than Cys and advantageously represents Asx or Glx, the preferred residue being Asn, X15 is any amino acid residue different from Cys and advantageously represents Gly, X17 is any amino acid residue different from Cys and advantageously represents Lys or Gln, Xl8 is Leu, Ile, Val, Ala or Tyr, the preferred residue being Ile, X ₂ o is Leu, Ile or Val, the preferred residue being Leu, X ₂ 4 is any amino acid residue other than Cys and advantageously represents Ala, Asx, Glx or Ser, the preferred residues being

Ala and Glu, Y25 is a Pro, Pro-X26 or Pro-X26-Tyr residue, the preferred residue being the monoamino acid residue Pro, X26 is any amino acid residue other than Cys and advantageously represents Arg, Ile, Leu, Val, Met or Trp, the preferred residue being Leu; and, (b) their non-toxic acid addition salts.

2. Peptide compound according to claim 1, characterized in that the peptide segment starting from X ₀₄ and ending towards X ₁₅ has a stable α helix.

3. Therapeutic composition, characterized in that it contains, in association with a physiologically acceptable excipient, at least one peptide of formula I according to claim 1 or one of its non-toxic addition salts.

4. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a drug inhibiting hematopoietic proliferation intended for use in therapy with respect to myeloproliferative syndromes.

5. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a cytoprotective medicament intended for use in therapy with respect to cytotoxic aggression, in particular for the anti-apoptotic protection of hematopoietic cells. 17

6. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a medullary expansion and / or purging medication intended for therapeutic use with regard to spinal cord insufficiency or in the event of a spinal transplant.

7. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a virustatic medicament intended for use in therapy with regard to viral affections.

8. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of an anti-inflammatory drug intended for use in therapy against inflammation.

9. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of the non-toxic acid addition salts for the preparation of 'an anti-angiogenesis drug intended for therapeutic use vis-à-vis a pathological angiogenesis.

10. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a drug that differentiates healthy cells from abnormal cells.

11. Use of a peptide characterized in that use is made of a peptide according to any one of claims 1 and 2 or to one of its non-toxic acid addition salts for the preparation of a drug that prolongs the S phase of the cell cycle.

12. Peptide compound according to claim 1 or 2, characterized in that it has, at its residues 7 to 11, a maximum value of helicity α which is greater than or equal to 0.12 unit.

13. Peptide compound according to claim 1 or 2, characterized in that it has a ratio R = α helix / β structures, which is greater than or equal to 2.