CN1732960A - As suppressing the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA phosphatidyl ethanolamine liposome - Google Patents

As suppressing the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA phosphatidyl ethanolamine liposome Download PDF

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CN1732960A
CN1732960A CN 200410074010 CN200410074010A CN1732960A CN 1732960 A CN1732960 A CN 1732960A CN 200410074010 CN200410074010 CN 200410074010 CN 200410074010 A CN200410074010 A CN 200410074010A CN 1732960 A CN1732960 A CN 1732960A
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liposome
trans
phosphatidyl ethanolamine
hiv
inhibitor
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江龙
赵红
李津如
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Institute of Chemistry CAS
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Abstract

The invention provides a kind of phosphatidyl ethanolamine liposome, it is as suppressing the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA inhibitor, this inhibitor also can be the mixture liposome of PHOSPHATIDYL ETHANOLAMINE and cholesterol, this phosphatidyl ethanolamine liposome obtains by the following method: with cephalin storing solution rotary evaporation, and use high-purity N 2After organic solvent dried up, make the cephalin dry film on the evaporator wall revolving, behind the second distillation water dissolution, obtain multilamelar liposome, the multilamelar liposome that makes again through supersound process, is made little unilamelar liposome, and then with microporous filter membrane it is carried out homogenize and handle.This inhibitor cost of material is cheap, suppresses effective, harmless.

Description

As suppressing the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA phosphatidyl ethanolamine liposome
Technical field
The present invention relates to a kind of as suppressing HIV-1 trans-activator (being called for short HIV-1 Tat) combines usefulness with trans-activating response sequence RNA (being called for short TAR RNA) phosphatidyl ethanolamine liposome.
Background technology
Acquired immune deficiency syndrome (AIDS) or acquired immune deficiency syndrome (AIDS) (Acquired Immunodeficiency Syndrome, be called for short AIDS) be a kind of viral communicate illness of at first finding in the U.S. in 1981, its cause of disease is a kind of retrovirus that can produce destructive power to human immune system, nineteen eighty-three called after HIV (human immunodeficiency virus) (HumanImmunodeficiency Virus is called for short HIV).After HIV infects human body, virus-specific ground is invaded and loss T lymphocyte causes the body cell immunologic injury, clinical initial representation is the symptomless virus carrier state, that continues develops into persistence lymph nodes of body as a whole enlargement syndrome, last concurrent various serious opportunistic infection and malignant tumor become acquired immune deficiency syndrome (AIDS), because of no specific treatment, case fatality rate is high, has become the formidable enemy of human health.So far the AIDS case load of five continents reports of spreading all over the world surpasses 2,000,000, and HIV the infected is nearly 50,000,000, and AIDS global death toll accumulative total reaches 22,000,000.In China, the HIV number of the infected surpasses 600,000, and still in rising trend.Acquired immune deficiency syndrome (AIDS) has become the public health and the hot spot of society that the whole world is paid close attention to.
HIV belongs to lentivirus (Lentivirus) Retroviridae, can be divided into two types of HIV-1 and HIV-2, wherein HIV-1 be cause the popular main diseases of global acquired immune deficiency syndrome (AIDS) because of, therefore, mainly carry out about the study on prevention of HIV at present at HIV-1.
Duplicating of human immunodeficiency virus type 1 (HIV-1) is subjected to trans-activator (trans-activating protein, Tat) regulate, Tat albumen can make virus mRNA level rising hundreds of times in the expression of transcription initiation and extending level trans-activation HIV-1LTR.The proteic effect of Tat is that (trans-activation-responsive region, TAR) specificity is in conjunction with realizing by being called the trans-activation conversion zone with a section of HIV-1 virus mRNA 5 ends.The small-sized albumen (Fig. 1) that Tat albumen is made up of 86 amino acid residues has two major function districts: rich cysteine district and base region, the latter is the specific recognition district of Tat and TAR.TAR RNA can form loop-stem structure (figure .2), and wherein the protrusion position that is formed by three nucleotide is and Tat albumen affinity and the bonded position of specificity, and annulus is that live body is needed when transcribing, but is not the land of Tat.
The coordination compound of HIV Tat and TAR RNA plays an important role to virus replication, therefore suppresses the important target spot that its interaction becomes design and exploitation AIDS resisting new drug.Because AIDS causes by the TAR RNA viruses, thus those and TAR RNA the bonded chemical compound of specificity is arranged will be effective inhibitors.And this inhibitor should be to human body nontoxic and be easy to absorbed.
Summary of the invention
The purpose of this invention is to provide a kind of conduct and suppress the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA phosphatidyl ethanolamine liposome, PHOSPHATIDYL ETHANOLAMINE is inexpensive, obtains easily, suppresses effective, and nontoxic.
For achieving the above object the present invention by the following technical solutions: a kind of HIV-1 of inhibition trans-activator combines usefulness with the trans-activating response sequence RNA inhibitor is a phosphatidyl ethanolamine liposome.Described inhibitor also can be the mixture liposome of PHOSPHATIDYL ETHANOLAMINE and cholesterol.
Described PHOSPHATIDYL ETHANOLAMINE also can be two or more a mixture of DSPE or DPPE or DMPE or DHPE or they, and the alkane carbon number is 10～18 in their molecules.The mol ratio of described PHOSPHATIDYL ETHANOLAMINE and cholesterol can be from 0.3-0.7: 0.7-0.3.
PHOSPHATIDYL ETHANOLAMINE content in cerebral tissue is a lot of, so claim cephalin again.Its structure as shown in Figure 3.
Natural cephalin is the mixture of various PHOSPHATIDYL ETHANOLAMINE, obtains the PHOSPHATIDYL ETHANOLAMINE of different R chain lengths after separating.Difference according to R chain length in the structure; PHOSPHATIDYL ETHANOLAMINE can be divided into 1; 2-distearyl acyl group PHOSPHATIDYL ETHANOLAMINE disteroyl phosphatidylethanolamine (DSPE); 1; 2-two palmityl PHOSPHATIDYL ETHANOLAMINE dipalmitoyl phosphatidylethanolamine (DPPE); 1; 2-two myristoyl PHOSPHATIDYL ETHANOLAMINE 1; 2-dimristoylphosphatidylethanolamine l (DMPE); 1; 2 two oenanthyl acylphosphatidyl ethanolamines 1,2-diheptnoyl phosphatidylethanolamine (DHPE) etc.Phosphatidyl ethanolamine liposome is the duplicature sphere that is formed by PHOSPHATIDYL ETHANOLAMINE, and the surface is amino, positively charged.It is a kind of harmless material.
Used liposome can adopt following method to obtain among the present invention:
With cephalin storing solution rotary evaporation, and use high-purity N 2After organic solvent dried up, can on the rotary evaporation wall, make the cephalin dry film.Behind the second distillation water dissolution, obtain multilamelar liposome.With the multilamelar liposome that makes in 80 ℃ of water-baths ultrasonic 1 hour, to prepare little unilamelar liposome.And then with 0.1 μ m filter membrane it is carried out homogenize and handle.Resulting circular liposome can be checked (see figure 4) with Electronic Speculum.
The common method of research protein and nucleic acid interaction is a lot, uses QCM (QCM) in this research.This method will be measured on the gilding that thing is fixed on QCM, need not the labelling determinand, and sensibility reciprocal is nanogram, and sensitivity is high.But the mass change of trace in the identifying of in situ detection protein HIV tat and TAR RNA.[Lin Lin, river dragon .DNA molecular recognition and sensing technology. chemistry circular, N0.5,261-267 (2001) .]
Assay method of the present invention is:
Utilize biotin (biotin) to combine the characteristics that speed is fast, combination stability is high with Avidin (avidin), earlier (neutravidin is the Avidin that does not contain glucosides with avidin or neutravidin, it is active consistent with parent, with the dissociation constant of biotin be K D=10 -15M) TAR RNA is fixed to the QCM gold-plated surface, utilizes the affinity of Tat (or cephalin liposome) and TAR RNA that Tat (or cephalin liposome) is fixed to again and be adsorbed with the QCM gold-plated surface.Its process is seen Fig. 5: among Fig. 5,
Figure A20041007401000051
Gold-plated surface, Do not contain the glucosides Avidin, *Biotin, TAR RNA,
Figure A20041007401000054
The DPPE liposome, HIVTat
Calculating TAR and Tat or TAR and the interactional method of cephalin liposome is:
Because act as specific effect between Tat or cephalin liposome and TAR, so Tat or cephalin liposome can reach the maximum combined ratio with TAR when high concentration.Therefore, the binding constant of Tat-TAR and cephalin liposome-TAR can be calculated according to similar Langmuir adsorption isotherm equation, that is:
Γ - Γ ∞ C ( K D + C ) - - - ( 1 )
Γ is Tat or cephalin liposome and the bonded amount of substance of TAR (mol), Γ ∞Be the Bmax of Tat or cephalin liposome and TAR, K DBe the dissociation constant of Tat-TAR or cephalin liposome-TAR, C is the concentration of Tat or cephalin liposome in the solution.(average diameter according to the cephalin liposome can be calculated its area.The area of 2 times cephalin liposome is the roughly quantity of forming the needed single cephalin of double-deck cephalin liposome divided by the area of single cephalin, thereby can be similar to the molecular weight of calculating the cephalin liposome).
With 1/ Γ and 1/C mapping, then slope is K D/ Γ ∞, cutting square is 1/ Γ ∞Thereby, can calculate binding constant.[H.Zhao，J.R.Li，L.Jiang，HIV-1?TAR?RNA-Tat?peptide?complexation?using?poly(acrylicacid)，BBRC，Vol?320/1?pp95-99(2004)]
Description of drawings
Fig. 1; The primary structure of HIV-1Tat.
Fig. 2: the secondary structure of HIV-1TAR RNA.
Fig. 3: the structural map of PHOSPHATIDYL ETHANOLAMINE.
Fig. 4: DPPE liposome Electronic Speculum figure
Fig. 5: molecular recognition process sketch map
Fig. 6: the change figure that the quality of QCM gold-plated surface adds with analyte
The quality change amount of QCM plane of crystal material and the graph of a relation of its concentration when Fig. 7 A:Tat combines with TAR RNA.
The graph of a relation of its concentration was measured in the quality change of QCM plane of crystal material when Fig. 7 B:DPPE liposome combined with TAR RNA.
The specific embodiment
Embodiment 1
Tat (GlyArgLysLysArgArgGlnArgArgArg) gives birth to worker's biological engineering company limited available from Shanghai, TAR RNA (biotin-5 '-GCCAGAUCUGAGCCUGGGAGCUCUCUGGC-3 ') available from the precious biotech firm in Dalian.
The DPPE storing solution that 1mM is commercially available (chloroform: rotary evaporation methanol=3: 1), and after with high-purity N 2 organic solvent being dried up, can on the rotary evaporation wall, make the cephalin dry film.Behind the second distillation water dissolution, obtain multilamelar liposome.With the multilamelar liposome that makes in 80 ℃ of water-baths ultrasonic 1 hour, to prepare little unilamelar liposome.And then with 0.1 μ m filter membrane it is carried out homogenize and handle.Resulting circular liposome can be checked with Electronic Speculum.
Earlier with the gold-plated wafer of QCM at 1mg mL -1Soaked 30 minutes in the neutravidin solution, to obtain the gold-plated wafer of QCM that neutravidin modifies.Successively with buffer solution and redistilled water flushing, measuring frequency.Then the gold-plated wafer of QCM that neutravidin is modified is 1.0 * 10 -6Soaked 60 minutes in the mol/L biotin-TAR RNA solution, to obtain the gold-plated wafer of QCM that biotin-TAR RNA modifies.After cleaning, measuring frequency.Again 1,2-dipalmitoylphosphatidylethanolamine (DPPE) liposome (concentration 7.0 * 10 -9Mol/L) or Tat (concentration is 1.0 * 10 -6Mol/L) soaked 60 minutes in the solution, clean the back measuring frequency again.The gold-plated wafer that will be adsorbed with cephalin liposome or Tat then immerses in Tat or the DPPE liposome solutions and soaked 60 minutes, cleans the back measuring frequency again.Experimental result as shown in Figure 6.
Among Fig. 6, abscissa is time (branch), and ordinate is mass change value (ng).
A curve: the absorption order of various materials on the gold-plated wafer of QCM; 1.neutravidin, 2.biotin-TAR, 3.DDPE liposome, 4.Tat
B curve: the absorption order of various materials on the gold-plated wafer of QCM; 5.neutravidin, 6.biotin-TAR, 7.Tat, 8.DPPE liposome.
Fig. 6 A curve shows behind the gold-plated wafer immersion of the QCM that is adsorbed with the TAR-DPPE coordination compound Tat solution, there is not tangible quality to change, illustrate that the DPPE liposome can suppress combining of Tat and TAR RNA, this may be because the interaction of DPPE liposome and TAR has changed the configuration of TAR.But after the gold-plated wafer of the QCM that will be adsorbed with the TAR-Tat coordination compound immerses the DPPE liposome solutions, can be observed tangible quality and change (Fig. 6 B curve), this may be owing to formed the TAR-Tat-DPPE ternary complex.
Tat or DPPE liposome can reach the maximum combined ratio with TAR when high concentration, our test has proved this point (Fig. 7 A, 7B), in Fig. 7 A, abscissa is concentration (μ mol/L), and vertical coordinate is mass change value (ng), in Fig. 7 B, abscissa is concentration (nmol/L), and ordinate is mass change value (ng).Therefore, the binding constant of Tat-TAR and DPPE liposome-TAR can be calculated according to formula (1).Can calculate the quantity of wherein contained DPPE molecule according to the average diameter of DPPE liposome, be 9.8 * 10 thereby can be similar to the mole of calculating the DPPE liposome 6
With 1/ Γ and 1/C mapping, its slope is K D/ Γ ∞, cutting square is 1/ Γ ∞Result of calculation shows, the surface combination constant (K of Tat-TAR D -1) be 3.9 * 10 5M -1, with the binding constant value basically identical of document [N.Tassew, M.Thompson, BiophysicalChemistry, 106, (2003) 241-252] report.And the surface combination constant (K of TAR-DPPE liposome D -1) be 7.8 * 10 6M -1, be 20 times of the former surface combination constant, illustrate that the affinity of DPPE liposome and TAR is better than Tat, can be used for suppressing HIV-1 Tat and combine with TAR RNA.
Embodiment 2
Present embodiment uses commercially available natural cephalin to prepare liposome, its preparation method such as embodiment 1.
Earlier with the gold-plated wafer of QCM at 1mg mL -1Soaked 30 minutes in the neutravidin solution, to obtain the gold-plated wafer of QCM that neutravidin modifies.Use buffer solution and secondary water distilled water flushing successively, measuring frequency.Then the gold-plated wafer of QCM that neutravidin is modified is 1.0 * 10 -6Soaked 60 minutes in the M biotin-TAR RNA solution, to obtain the gold-plated wafer of QCM that biotin-TAR RNA modifies.After cleaning, measuring frequency.In natural cephalin liposome solutions, soaked 60 minutes again, clean the back measuring frequency again.The gold-plated wafer that will be adsorbed with cephalin liposome or Tat then immerses in Tat or the natural cephalin liposome solutions and soaked 60 minutes, cleans the back measuring frequency again.Experimental result shows behind the gold-plated wafer immersion of the QCM that is adsorbed with the natural cephalin coordination compound of the TAR-Tat solution, there is not tangible quality to change, illustrate that natural cephalin liposome can suppress combining of Tat and TAR RNA, this may be because the interaction of natural cephalin liposome and TAR has changed the configuration of TAR.But after the gold-plated wafer of the QCM that will be adsorbed with the TAR-Tat coordination compound immerses natural cephalin liposome solutions, can be observed tangible quality and change, this may be owing to formed the natural cephalin ternary complex of TAR-Tat-.
The surface combination constant K a that can calculate Tat-TAR according to approximate Langmuir adsorption isotherm equation is 3.9 * 10 5M -1And the surface combination constant K of the natural cephalin liposome of TAR- aBe 9.6 * 10 6M -1, be 24 times of the former surface combination constant, illustrate that the affinity of natural cephalin liposome and TAR is better than Tat.Can be used for suppressing HIV-1 Tat combines with TAR RNA.
Embodiment 3
Present embodiment uses commercially available cholesterol and 1, and 2-two myristoyl PHOSPHATIDYL ETHANOLAMINE (DMPE) prepare the mixing liposome, its preparation method such as embodiment 1
Earlier with the gold-plated wafer of QCM at 1mg mL -1Soaked 30 minutes in the avidin solution, to obtain the gold-plated wafer of 0CM that avidin modifies.Successively with buffer solution and the flushing of secondary water, measuring frequency.Then the gold-plated wafer of QCM that avidin is modified is 1.0 * 10 -6Soaked 60 minutes in the M biotin-TAR RNA solution, to obtain the gold-plated wafer of QCM that biotin-TAR RNA modifies.After cleaning, measuring frequency.Soaked 60 minutes in the mixing liposome solutions of DMPE and cholesterol, the molar fraction of DMPE and cholesterol is 0.5: 0.5 again.Clean the back measuring frequency again.The gold-plated wafer that will be adsorbed with mixing liposome or Tat then immerses in Tat or the DMPE liposome solutions and soaked 60 minutes, cleans the back measuring frequency again.After the gold-plated wafer of the QCM that is adsorbed with TAR-mixing liposome coordination compound immersed Tat solution, do not have tangible quality to change, illustrate that the mixing liposome can suppress combining of Tat and TARRNA.But after the gold-plated wafer of the QCM that will be adsorbed with the TAR-Tat coordination compound immerses and mixes liposome solutions, can be observed tangible quality and change, this may be owing to formed TAR-Tat-mixing liposome ternary complex.
Can calculate the surface combination constant K of Tat-TAR according to Langmuir adsorption isotherm equation aBe 3.9 * 10 5M -1And the surface combination constant K of TAR-mixing liposome aBe 5.7 * 10 6M -1, be 15 times of the former surface combination constant, illustrate that the mixing liposome that contains cholesterol and the affinity of TAR are better than Tat, can be used for suppressing HIV-1 Tat and combine with TAR RNA.
Sequence table
＜110〉Institute of Chemistry, Academia Sinica
＜120〉as suppressing the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA phosphoric acid acyl ethanolamine liposome
<130>
<160>2
<170>PatentIn?version?3.1
<210>1
<211>10
<212>PRT
＜213〉synthetic
<400>1
Gly?Arg?Lys?Lys?Arg?Arg?Gln?Arg?Arg?Arg
1 5 10
<210>2
<211>29
<212>RNA
＜213〉synthetic
<400>2
gccagaucug?agccugggag?cucucuggc

Claims (5)

1. one kind is suppressed the HIV-1 trans-activator combines usefulness with the trans-activating response sequence RNA inhibitor, and it is characterized in that: described inhibitor is a phosphatidyl ethanolamine liposome.
2. inhibition HIV-1 trans-activator as claimed in claim 1 combines the inhibitor of usefulness with the trans-activating response sequence RNA, it is characterized in that: described inhibitor is the mixture liposome of PHOSPHATIDYL ETHANOLAMINE and cholesterol.
3 inhibition HIV-1 trans-activators as claimed in claim 1 or 2 combine the inhibitor of usefulness with the trans-activating response sequence RNA, it is characterized in that: described PHOSPHATIDYL ETHANOLAMINE is two or more a mixture of DSPE or DPPE or DMPE or DHPE or they, and the alkane carbon number is 10～18 in their molecules.
4. inhibition HIV-1 trans-activator as claimed in claim 2 combines the inhibitor of usefulness with the trans-activating response sequence RNA, it is characterized in that: wherein the molar fraction of PHOSPHATIDYL ETHANOLAMINE and cholesterol is from 0.3-0.7: 0.7-0.3.
5 inhibition HIV-1 trans-activators as claimed in claim 1 or 2 combine the inhibitor of usefulness with the trans-activating response sequence RNA, it is characterized in that: it is the liposome that obtains by the following method, with cephalin storing solution (chloroform: rotary evaporation methanol=3: 1), and use high-purity N 2After organic solvent dried up, can on the rotary evaporation wall, make the cephalin dry film, behind the second distillation water dissolution, obtain multilamelar liposome, with the multilamelar liposome that makes in 80 ℃ of water-baths ultrasonic 1 hour, preparing little unilamelar liposome, and then with 0.1 μ m filter membrane it is carried out homogenize and handle, the concentration of its cephalin storing solution is from 0.5-2.0mM/L.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101234113B (en) * 2007-02-01 2011-10-26 中国人民解放军第二军医大学 Anti-tumor small molecular compound targeting to phosphatidylethanolamine conjugated protein 4 of human

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101234113B (en) * 2007-02-01 2011-10-26 中国人民解放军第二军医大学 Anti-tumor small molecular compound targeting to phosphatidylethanolamine conjugated protein 4 of human

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