Top > Search of International Patents > CHOLESTEROL-EFFLUX PEPTIDE

CHOLESTEROL-EFFLUX PEPTIDE

Foreign code F110005871
File No. S2011-0369-N0
Posted date Nov 9, 2011
Country WIPO
International application number 2010JP065070
International publication number WO 2011027839
Date of international filing Sep 2, 2010
Date of international publication Mar 10, 2011
Priority data
  • P2009-202273 (Sep 2, 2009) JP
Title CHOLESTEROL-EFFLUX PEPTIDE
Abstract Disclosed is a peptide which has an effect of promoting cholesterol efflux and another effect of generating HDL. This cholesterol-efflux peptide has an effect of generating HDL in addition to the effect of promoting cholesterol efflux. A medicinal composition that comprises the aforesaid cholesterol-efflux peptide as the main active ingredient is useful in promoting cholesterol efflux, increasing serum HDL concentration, activating LCAT and promoting RCT and, therefore, can be used for preventing and treating cardiovascular diseases, for example, angina, hypertension, hyperlipemia such as hypercholesterolemia and arterial sclerosis such as atherosclerosis, cardiovascular diseases relating to cardiovascular disorders that are induced by medical treatments using a balloon, a stent or the like such as re-stenosis caused by atherosclerotic plaque, and disorders related thereto.
Outline of related art and contending technology BACKGROUND ART
The seals -, and living, maintained in progressing in the essential components. However, the alcohol itself -, type 1 from lipids, not dissolved by the water since the composed mainly of blood, the blood as it cannot be transported. Therefore, the seals -, in vivo, of binding lipoproteins that apolipoprotein complex in the state of being carried in the blood. The lipoproteins are, in general, apolipoprotein the density of the particles, and specific gravity by, chylomicrons, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) are broadly classified into one of the 4.
Among these lipoproteins, low density lipoprotein (LDL) and high density lipoprotein (HDL) in blood is the main - involved in transportation of the seals. Low density lipoprotein (LDL) is, carried to the cell as a roll - the important to play a role. On the other hand, the high density lipoprotein (HDL), and transported to the liver from the cells as a roll - important role to play. Therefore, in the normal state, and is balanced and LDL and HDL, and transfer of the seals and removing - is properly carried out such that there is no problem. However, once the balance of the LDL and HDL and, in the body of the seals - becomes unable to control, within the various abnormal, failure, due to disease and the like are known.
- In particular low density lipoprotein (LDL) is preferred that the maximum of the seals, such as arteriosclerosis risk factors of cardiovascular disease is extremely high in - well known. In this sense, low density lipoprotein (LDL) - paraxyleneglycol is' bad paraxyleneglycol - ' which is commonly referred to as why. Therefore, for the prevention or treatment of a cardiovascular disorder first as an option, this LDL - lowering paraxyleneglycol paraxyleneglycol LDL - lowering therapy is applied. This LDL - lowering therapy paraxyleneglycol is, in general, such as - lowering drugs such as statins of is carried out by a roll. However, such LDL - lowering therapy paraxyleneglycol only, the onset of cardiovascular disease cannot be suppressed sufficiently in has not been set (for example, see non-patent document 1).
On the other hand, as described above, the high density lipoprotein (HDL), and transported to the liver from the cells as a roll - "- so-called paraxyleneglycol reverse transfer system" an important role in, or organization of the seals as - - important to play a role. From this, high density lipoprotein (HDL) - seals, low density lipoprotein (LDL) - paraxyleneglycol is' bad paraxyleneglycol - 'whereas commonly referred to as a, ' - good paraxyleneglycol ' are commonly referred to as a. Therefore, high density lipoprotein (HDL) blood levels of the seals -, value that is higher than a predetermined concentration is required. On the other hand, the seals HDL - and a low value than a predetermined value, a sufficient amount of liver paraxyleneglycol - not conveyed to the decomposition ceases and, as a result the blood with the increasing amount paraxyleneglycol -, 1 - cardiovascular disease risk factors shown to be one of which (for example, the non-patent document 2, reference 3). Therefore, the next paraxyleneglycol LDL - lowering therapy as a therapeutic target, action-enhancing of the seals HDL - hasbeenattractingattentioninrecentyears therapy (for example, the non-patent document 4, reference 5).
Current, of the seals HDL - enhancing therapy includes, as an increase of the seals HDL - statins, such as - transfer protein inhibitor therapy drug administration has been performed. However, they all have a sufficient effect is not necessarily increased. In other words, currently available paraxyleneglycol - prevention, the therapeutic agent is, satisfactory HDL increase paraxyleneglycol - can be advantageous effects as those in has not been set (for example, see non-patent document 1).
On the other hand, the major protein component of HDL or apolipoprotein A-I is (ApoA-I), prevent or ameliorate atherosclerosis atherosclerosis - indicating that the in vivo experiments (in vivo) de - wherein data have been reported. That is, in humans, serum ApoA-I and impaired proteasome - (SEQ ID NO:1) have an inverse relationship formed (for example, the non-patent document 2, 6, Patent Document 1 reference) and, - the component of the impaired HDL to reduce the risk of atherosclerosis (for example, the non-patent document 7, patent document 1 reference) have been revealed. In addition, the HDL or ApoA-I, causing regression of the track - also be clear that has been (for example, non-patent document 8, reference 9). These findings suggest that, HDL and its major protein component is apolipoprotein A-I is an apolipoprotein (ApoA-I) itself and therapeutic target for the research and development have been performed.
As a result of research and development of these, is a synthetic scheme to enhance HDL (reconstituted high density lipoprotein HDL: rHDL) made of various types (for example, see non-patent document 10). RHDL such as, for example, a series of processing human plasma or serum processing (ultracentrifugation) HDL isolated by ultracentrifugation (for example, see non-patent document 11), a conventional purification means such as chromatography - purified using apolipoprotein A-I(ApoA-I) (for example, see Patent Document 2 and Non-Patent Document 12) and the like. Other, ApoA-I gene or variant thereof in place of the set made by (for example, Patent Document 1, reference 13 and non-patent document 5).
As described above is made HDL or ApoA-I, lipid in combination with various synthetic HDL (rHDL) are prepared. RHDL such as, for example, the plasma ApoA-I and soybean lecithin made from rHDL (Patent Document 6), and ApoA-I, extracted from egg or soybean phosphatidylcholine rHDL made from (Patent Document 7), and ApoA-I and made from dimyristoylphosphatidylcholine (DMPC) (for example, see non-patent document 14) rHDL and the like can be exemplified. In addition to these, made by the inventors as rHDL, apolipoprotein A-I and palmitoyl (ApoA-I) -2 - and 1 - made from oleoylphosphatidylcholin rHDL (POPC) (POPC/ApoA-I) (for example, the non-patent document 1, reference 15) or, the active rHDL phospholipid (POPC/ApoA-I) which is one of the sphingosine -1 - phosphate (sphingosine-1-phosphate: SIP) was added new rDHL(POPC/SIP/ApoA-I) and the like (for example, see non-patent document 3). Made by the present inventors rHDL (POPC/ApoA-I) is, by co-culture with di - macro facet, such an extra accumulated intracellularly paraxyleneglycol - was confirmed to be extracted (for example, non-patent document 1, reference 3). In addition, this new rHDL(POPC/SIP/ApoA-I) is, in vitro in addition to the operation of drawing paraxyleneglycol -, tube formation of endothelial cells to the action of a coronary artery shown (for example, see non-patent document 15). In addition to such a result, rHDL (infusion) (ApoA-I) by injection, and anti-inflammatory effect in high density lipoprotein plasma out paraxyleneglycol - increased ability is obtained from the result, the injection of rHDL (infusion) (ApoA-I) is, multi-potential atherosclerosis - formed possess a preventive effect was also shown (for example, see non-patent document 16). From the results for such rHDL, attention has been noted that rHDL.
However, on the one hand, apolipoprotein A-I or HDL (ApoA-I) is actually used as the pharmaceuticals, various problems have been in relief that can be used. Is ApoA-I, composed of 243 amino acid residues of a protein from the large molecules, difficult and complicated manufacturing method, and the manufacturing cost is also high, stability during storage, or the delivery of active agents in vivo half-life such as in the manufacturing difficulties as well as reproducibility must be to solve such a problem is also found that the (for example, see Patent Document 1).
On the other hand, the carry-out paraxyleneglycol ApoA-I itself - and has the effect that is a strong basis from, the structure of the ApoA-I(mimic) or activity of various peptides to the pseudo-have been produced. For design of the pseudo peptide, key activity ApoA-I, the secondary structure of the unique characteristics of this protein in the presence of a large number of iterations, class A-type amphipathic α helix that depend on the reports (for example, see non-patent document 17) based on the, class A-type amphipathic α helix form have been focused on.
Peptidomimetic ApoA-I such as, for example, so as to form a amphipathic α helix Glu, Lys Leu and regularly arranged completely and only residues 22 and 41% of ApoA-I peptide sequence homology with the 198-2192 fragment (peptide ELK) (for example, the non-patent document 18, reference 19); LAP 16-24 amino acid residues is referred to as ApoA-I peptide sequence homology model does not have the amphiphilic peptides (for example, see non-patent document 20); ApoA-I helices with sequence homology to the amino acid residue peptide is not 18-24 (for example, see non-patent document 21); human ApoA-I based on an order based on the helix of the common peptide has the amino acid residue 22 (for example, the non-patent document 22, reference 23) and the like. However, this ApoA-I to pseudo-peptide is made, both ApoA-I is not the same degree of activity, the activity of said useful as medicaments as no indication (for example, see Patent Document 1).
In addition to the above-mentioned ApoA-I peptidomimetic, amphiphilic lipid in the presence of residues 15-29 were to form α amino acid residues, preferably 22 amino acid residues of the 'core' ApoA-I peptide agonist of a number of fabricated (for example, Patent Document 1, reference 5). These ApoA-I agonist, and is crucial for activity have been proposed (Pro(P) Val(V) Leu(L) Asp(D) Glu(E) Phe(F) Arg(R) Glu(E) Lys(K) Leu(L) Asn(N) Glu(E) Glu(E) Leu(L) Glu(E) Ala(A) Leu(L) Lys(K) Gln(Q) Lys(K) Leu(L) Lys(K) 22-mer consensus sequence of: SEQ ID NO:2) (and references cited as SEQ ID NO:75. Hereinafter, 'common 22-mer' that) in the primary sequence of by changing the particular amino acid residues, natural ApoA-I are close to or greater than the activity of the synthetic peptide activity described is obtained (for example, Patent Document 1, reference 8). Further, the common 22-mer one charged amino acid residues in the peptide 3 (Glu-5, and Glu-13 Lys-9) to, by substituting hydrophobic leucine residues, could not be predicted from the literature ApoA-I a pseudo peptide structure and function of the characteristics described is obtained (for example, Patent Document 1, reference 8). These pseudo-peptides, yet pharmaceutically useful degree of activity does not have the recorded.
Thereon, (ApoA-I) apolipoprotein ApoA-I is, only the center mediate ABCA1 (ATP-binding castle transporter A1) lipid while promoting the discharge can be, for production of ejection or lipid HDL in order to demonstrate that functional interactions is, between ApoA-I and ABCA1 the amino acid sequence of sufficient length is required, the length is 220-231 residues has been reported (non-patent document 24).
Scope of claims (In Japanese)請求の範囲 [請求項1]
一般式[I]:
H-X1-X2-X3-His-Leu-X4-Thr-Leu-X5-Glu-Lys-Ala-
X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-
X18-OH                 [I]
  [式中、X1はAla、単結合("-")または一般式[Ia]:
  X1e-X1d-X1c-X1b-X1a-      [Ia]
 (式中、X1aはAlaまたは単結合("-")を意味し 、X1bはLys、Argまたは単結合("-")を意味し、X1cはAlaまたは単結合("-")を意味し、X1dはHisまたは単結合("-")を意味し、およびX1eはTyrまたは単結合("-")を意味する。)を意味し、
 X2はThr、Leu、LysまたはSerを意味し、
 X3はGlu、ThrまたはAspを意味し、
 X4はSer、PheまたはLysを意味し、
 X5はSer、Tyr、Trp、Phe またはGlyを意味し、
 X6は単結合("-")、Lys、LeuまたはArgを意味し、
 X7は単結合("-")、ProまたはLysを意味し、
 X8は単結合("-")またはAlaを意味し、
 X9は単結合("-")、Pheまたは Leuを意味し、
 X10は単結合("-")、Glu、GlnまたはAspを意味し、
 X11は単結合("-")またはAspを意味し、
 X12は単結合("-")またはLeuを意味し、
 X13は単結合("-")、Arg、LeuまたはGlyを意味し、
 X14は単結合("-")、GlnまたはHisを意味し、
 X15は単結合("-")、Gly、LysまたはSerを意味し、
 X16は単結合("-")、LeuまたはHisを意味し、
 X17は単結合("-")、Leu 、Metまたは一般式[Ib]:
   X17a-X17b-X17c-X1d          [Ib]
 (式中、X17aは単結合("-")、Leu またはMetを意味し、X17bはPro、Tyrまたは単結合("-")を意味し、X17c はValまたは単結合("-")を意味し、ならびにはX1dはLeuまたは単結合("-")を意味する。)を意味し、
 ただし、記号X1a-X1eおよび記号X17a-X17dがいずれも単結合("-")を意味する場合は、それらの単結合は全体として1個の単結合("-")を意味し、また、同時にX1がAla、X2がThr、X3がGlu、X4がSer、X5がSer、X6がLys、X7がPro、X8がAla、X9がLeu、X10がGlu、X11がAsp、X12がLeu、X13がArg、X14がGln、X15がGly、X16がLeu、およびX17がLeuである場合を除くものとする。]
で表されるペプチド、または一般式[II]:
A -X20 (X21-OH) - A [II]
[式中、Aは、一般式[IIa]:
H-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-
X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-
X44-X45-X46-                  [IIa]
 (式中、X22はAlaまたはValを意味し、X23はThr, Leu, LysまたはSerを意味し、X24はGlu, ThrまたはAspを意味し、X25はHisまたはSerを意味し、X26はLeuまたはPheを意味し、X27はSer, PheまたはLysを意味し、X28はThrまたはValを意味し、X29はLeuまたはSerを意味し、X30はSer, Gly, Phe, TyrまたはTrpを意味し、X31はGluまたはLeuを意味し、X32はLysまたはSerを意味し、X33はAlaを意味し、X34はLys, Leu, Argまたは単結合("-")を意味し、X35はPro, Glu, Lysまたは単結合("-") を意味し、X36はAla, Gluまたは単結合("-")を意味し、X37はLeu, Tyrまたは単結合("-")を意味し、X38はGlu, Gln, Asp, Thrまたは単結合("-")を意味し、X39はAsp, Lysまたは単結合("-")を意味し、X40はLeu, Lysまたは単結合("-")を意味し、X41はArg, Gly, Leuまたはを単結合("-")を意味し、X42はGln, Leu, Lys, Hisまたは結合("-")を意味し、X43はGly, Leu, Lys, Serまたは結合("-")を意味し、X44はLeu, Hisまたは結合("-")を意味する。)を意味し、
X20はLys等のアミノ酸残基を意味し、および
X21はLeuまたはAla等のアミノ酸残基を意味する。)
で表される二量体;または一般式[III]:
(A) 2-X22 (X23-OH)-(A) 2 [III]
(式中、Aは前記と同じ意味を有し、
    X22 はLys等のアミノ酸残基を意味し、および
    X23はLeuまたはAla等のアミノ酸残基を意味する。)
で表される四量体からなるペプチド。

[請求項2]
 請求項1に記載のペプチドであって、該ペプチドがコレステロ-ル搬出作用を有していることを特徴とするペプチド。

[請求項3]
 請求項1または2に記載のペプチドであって、該ペプチドがHDL新生作用をさらに有していることを特徴とするペプチド。

[請求項4]
 請求項1ないし3のいずれか1項に記載のペプチドであって、ペプチド番号1~16のいずれか1つで表されることを特徴とするペプチド。

[請求項5]
 請求項1に記載のペプチドを有効成分として含有することを特徴とする医薬組成物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • Fukuoka University
  • Inventor
  • SAKU Keijiro
  • ANDO Setsuko
  • UEHARA Yoshinari
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

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