CN102657652A - Novel uses of bisbenzylisoquinoline alkaloid derivative or analogue of general formula I - Google Patents
Novel uses of bisbenzylisoquinoline alkaloid derivative or analogue of general formula I Download PDFInfo
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Abstract
The invention provides a use of a bisbenzylisoquinoline alkaloid derivative or analogue to prepare medicine medicines for treating diabetic nephropathy. The bisbenzylisoquinoline alkaloid derivative of general formula I provided by the invention by relieving glomerular basement membrane thickening, reduces foot process fusion of glomerular epithelial cells and restores mechanical barrier and charge barrier of glomerulus, thus reducing protein leakage, having a good therapeutic effect on diabetic nephropathy (stage III or stage IV) patients, reducing 24h micro-albumin (UAE) and 24h urine protein (UPQ), having a good inhibitory effect on the albuminuria symptom of the diabetic nephropathy, and providing a new choice for the clinical treatment of the diabetic nephropathy.
Description
Technical field
The present invention relates to bisbenzylisoquinoline alkaloid derivant or the analog purposes in preparation treatment medicine for treating diabetic nephropathy, belong to field of medicaments.
Background technology
Diabetic nephropathy is one of severe complications of diabetes, is again the ESRD main cause.Along with the change of expanding economy and life style, the sickness rate of diabetes raises gradually, does not still have Therapeutic Method preferably at present.Other pathological changes of diabetic nephropathy are that glomerular basement membrane thickens, glomerular epithelium cell podocytic process merge and since extracellular mesentery substrate increase due to glomerule increase.Fibrosis in the renal tubules atrophic kidney can appear in the terminal stage of a disease.Diabetic duration is person's about 50% concurrent diabetic nephropathy more than 10 years.At present, risk factor is controlled in the treatment of diabetic nephropathy on the one hand, blocks the key link in the diabetic nephropathy development on the other hand.
At present, though the pathogeny of diabetic nephropathy is unclear fully as yet, glomerular basement membrane thickens, and fusion of glomerular epithelium cell podocytic process and glomerule mechanical barrier and electrostatic barrier are impaired, and causing spilling of urine protein is its main cause.The glomerular filtration barrier is the important structure of glomerule, from inside to outside is followed successively by endothelium fenestra layer, GBM (GBM), podocyte and slit diaphragm (GPSD) thereof, and wherein GBM and GPSD stop albumen to spill topmost two-layer.GBM mainly plays the electric charge barrier action, and GPSD mainly brings into play the mechanical barrier effect, and any change of their 26S Proteasome Structure and Function all can destroy the integrity of glomerular filtration barrier, causes albumen to spill.Nephridial tissue podocyte correlation molecule nephrin, podocin and GBM go up the correlation molecule heparitinase, and (heparanase, variation HPSE) can reflect the variation of mechanical barrier and electrostatic barrier.Therefore, if can alleviate glomerular basement membrane and thicken, reduce glomerular epithelium cell podocytic process and merge, recovering glomerule mechanical barrier and electrostatic barrier is finally to reduce the key that urine protein spills, and also is the important target spot of treatment diabetic nephropathy.
Bisbenzylisoquinoline alkaloid derivant shown in the general formula I,
General formula I
This compounds comprises liensinine, isoliensinine, (-)-Neferine etc.Discover at present; This compounds has multiple biological activity; For example; Number of patent application: CN03136949.9 discloses this compounds fibroblast has been had significant inhibitory effect in this application, can further develop the particularly medicine in the corium fabric disease of treatment fibrosis diseases related.Number of patent application: 201010199365.3, point out in this application that this compounds can be used for suppressing 5, the prostate body of gland is dwindled, remove the symptom of blocking of prostatic hyperplasia rapidly, also can treat seborrheic alopecia, acne.Discoveries such as Pan Yang; (-)-Neferine to artificial diabetes and obese rat have certain blood sugar lowering and blood lipid regulation effect (Pan Yang, etc., Plumula Nelumbinis and Nef are to the influence of artificial diabetes and obese rat model; " Nanjing University of Traditional Chinese Medicine's journal ", 2003 19 4 phases of volume).
At present, do not see that also bisbenzylisoquinoline alkaloid derivant shown in the general formula I and chemical compounds such as liensinine, isoliensinine and (-)-Neferine are used to treat the report of diabetic nephropathy.
Summary of the invention
The object of the present invention is to provide the new purposes of a kind of bisbenzylisoquinoline alkaloid derivant or analog.
The invention provides described bisbenzylisoquinoline alkaloid derivant of general formula I or the analog purposes in preparation treatment diabetic nephropathy drugs:
General formula I
Wherein
R
1, R
2, R
3, R
4, R
5Be H, CH
3, CH
3CO, CH
3CH
2CO, CH
3CH
2CH
2CO;
Q
1, Q
2For-NH-,-NCH
3-, N → O ,-NR
+-.
Wherein, said medicine is that the treatment diabetic nephropathy III phase is or/and the medicine of IV phase.
Wherein, described medicine is to alleviate glomerular basement membrane to thicken, and reduces glomerular epithelium cell podocytic process and merges or/and recover the medicine of glomerule mechanical barrier and electrostatic barrier.
Wherein, described medicine is the albuminuretic medicine of treatment.
Wherein, Q
1, Q
2For-NCH
3-.
Further, R
1, R
2, R
3, R
4, R
5Be H or CH
3
Further preferably, described bisbenzylisoquinoline alkaloid derivant or analog are:
Wherein, described medicine is to be active component by described bisbenzylisoquinoline alkaloid derivant of the general formula I of effective dose or analog, adds the preparation that acceptable accessories or complementary composition are prepared from.
Further, described preparation is oral formulations, ejection preparation.
Further, described preparation is tablet, oral liquid, pill, capsule, injection, unguentum, tincture, powder, electuary, suppository, cream, preparation capable of permeating skin or health food and food additive.
The bisbenzylisoquinoline alkaloid derivant of general formula I of the present invention; Thicken through alleviating glomerular basement membrane; Reduce glomerular epithelium cell podocytic process and merge, recover glomerule mechanical barrier and electrostatic barrier, thereby reduce proteic spilling; Diabetic nephropathy (III phase or IV phase) patient there is therapeutical effect preferably; Can reduce 24h microalbumin (UAE) and 24h urine protein (UPQ), the albuminuria symptom of diabetic nephropathy had good inhibition effect, for the clinical treatment diabetic nephropathy provides new selection.
The specific embodiment
In the specific embodiment of the invention, used liensinine, isoliensinine, (-)-Neferine all can obtain through buying the commercial goods, and through structure determination are:
Detect through HPLC, the purity of each chemical compound all >=98% again.
The clinical experiment of embodiment 1 bisbenzylisoquinoline alkaloid derivant of the present invention
1.1 receive the reagent thing
Liensinine, isoliensinine, (-)-Neferine are distinguished encapsulated, make Cebo-Caps (containing equivalent starch) simultaneously, and the capsule outward appearance is all consistent with the captopril capsule with color.
1.2 experimental subject
Have 100 routine diabetic nephropathyes (III phase or IV phase) patient and get into research, random assortment to liensinine group 30mg/Tid, isoliensinine group 30mg/Tid, (-)-Neferine group 30mg/Tid, captopril Capsules group, and placebo group/Tid.Each group does not have significance (P＞0.05) in sex, age, the course of disease and clinical symptoms difference before going into group, has comparability.
Each is organized the patient and all meets following condition: (1) meets diabetic nephropathy, belongs to III phase or IV phase, urine protein≤3.5g/24h patient by the Mogensen diabetic nephropathy by stages; (2) continuous 3 the mensuration＞30mg/24h of 24h urinaryalbumin (3) get rid of reasons such as urine protein that constitutional nephropathy and other kidney disease, essential hypertension, tumor, heating and strenuous exercise etc. cause increases.
1.3 Therapeutic Method
All experimenters are constant in the Primary Care of duration of test diabetes.Each organize investigational agent all by 1/inferior, 3 times/d, oral; The captopril Capsules group: 1 (12.5mg)/inferior, 3 times/d, oral; Placebo group: 1 of simulant capsule/inferior, 3 times/d, oral; Statistics curative effect after 8 weeks of treatment.
1.4 curative effect index is observed and method
Observation item comprises urine 24h microalbumin (UAE, mg24h
-1), 24h urine protein quantitation (UPQ, mg24h
-1), adopt OLYMPUS AU640 automatic clinical chemistry analyzer, before the treatment when finishing the course of treatment (8 week) respectively check 1 time.Result of the test is seen table 1.
UAE and UPQ curative effect are relatively before and after the treatment of table 1 diabetic nephropathy
Annotate: compare with placebo group,
*P＜0.05,
*P＜0.01; Compare with the captopril group,
#P＜0.05,
##P＜0.01;
On duration of test diabetes Primary Care basis of invariable; Each organizes investigational agent has therapeutical effect preferably to diabetic nephropathy (III phase or IV phase) patient; Can reduce 24h microalbumin (UAE) and 24h urine protein (UPQ), show that the bisbenzylisoquinoline alkaloid derivant can alleviate the albuminuria symptom of diabetic nephropathy patient preferably.Wherein liensinine, isoliensinine, (-)-Neferine curative effect are good, are superior to positive controls.
The drug efficacy study of embodiment 2 bisbenzylisoquinoline alkaloid derivants of the present invention
1 materials and methods
1.1 experiment material
1.1.1 animal
Cleaning level healthy male Sprague-Dawley (SD) rat, body weight 180～200g is available from Sichuan University's West China Experimental Animal Center.In room temperature (22 ± 1) ℃, relative humidity (55 ± 5) %, periodicity of illumination 12h～12h environment, adapt to and test after raising 1wk.
1.1.2 medicine
Liensinine, isoliensinine, (-)-Neferine.Irritate stomach with the normal saline preparation during use; Captopril (captopril) sheet, Shanghai Sino-U.S. executes expensive precious pharmaceutcal corporation, Ltd and produces lot number: 1006041.
1.1.3 main agents
Streptozotocin (Streptozotocin, STZ), Sigma company faces with before being dissolved in the 0.01mol/L citrate buffer, and pH 4.5; The Mus nephrin of the rabbit Chinese People's Anti-Japanese Military and Political College, podocin and HPSE polyclonal antibody, Wuhan doctor's moral; The goat anti-rabbit igg and the lowlenthal serum confining liquid of biotin labeled goat anti-rabbit igg, HRPO (HRP) labelling, Beijing Bo Aosen bio tech ltd; Total RNA from animal tissues extracts test kit (centrifugal column type) and RT-PCR test kit, day root biochemical technology company limited; PCR primer, Shanghai are given birth to worker's biological engineering technical service affair company limited.
1.2 method
1.2.1 the foundation of animal model and grouping
Rat single intraperitoneal injection 1%STZ 65mg/kg, tail vein blood behind the 72h, blood glucose meter is measured whole blood blood glucose, with the selected diabetes rat model of blood glucose >=11.1mmol/L person behind the empty stomach 12h.Normal control group (n=10) single intraperitoneal injection equivalent citrate buffer.The rat of choosing after the modeling success is divided into liensinine group 2mgkg at random
-1(n=10), isoliensinine group 2mgkg
-1(n=10), (-)-Neferine group 2mgkg
-1(n=10), captopril group (n=10) contains captopril 3.6mg/kg and (converts according to people and Mus body surface area; Be equivalent to the 37.5mg/d that is grown up) the filling stomach; Diabetic nephropathy model group (n=10), normal control group (n=10), the oral equivalent normal saline of normal control group and model group.Be administered once every day, continues 8wk.All rats all feed standard diet at whole experimental session, freely drink water, and do not use insulin, keep bedding and padding dry, and blood monitoring blood glucose is got in docking regularly, observes 8wk.
1.2.2 specimen collection
Accurately collect the 24h urine before putting to death, be stored in urine protein to be measured and urinaryalbumin content in-20 ℃ of refrigerators after the centrifugal packing.Tail vein blood, blood glucose meter are measured the whole blood blood sugar level behind the empty stomach 12h.Weigh in.The last administration after 24 hours cervical vertebra dislocation put to death rat, take out the bilateral kidney rapidly, clean repeatedly with the normal saline of 4 ℃ of pre-coolings, go peplos filter paper to blot the left kidney of weighing behind the bloodstain, the ratio of left kidney weight (KW) and body constitution amount is as the index of kidney index (KI).Right kidney vertical profile is two, and half is fixed with 10% neutral formalin, stays and does pathology, immunohistochemistry research.Second half is fixed with 2.5% glutaraldehyde, stays and does transmission electron microscope research.Left side kidney places the frozen pipe of DEPC water treatment, changes-70 ℃ of refrigerator RT-PCR to be measured after the liquid nitrogen deep colling over to.
1.2.3 assay method
Twenty-four-hour urine protein quantification (Upro) adopts the Coomassie brilliant blue method; Urinaryalbumin is measured, and adopts radioimmunology, by the special-purpose urine protein test kit of Beijing North rat that biotechnology research provides, detects with the automatic γ immunity of SN-682 type enumerator.
1.2.4 pathological examination
Light microscopy specimen is made: nephridial tissue is carried out HE dyeing through routine dehydration, embedding, slice thick 4 μ m.
Electron microscope specimen is made: sample pre-fixes through 3% glutaraldehyde, and 1% Osmic acid. is fixing again, and acetone dewaters step by step, Epon812 embedding, semithin section optical alignment, ultrathin section, acetic acid uranium and lead citrate double staining, the H-600IV of Hitachi type transmission electron microscope observing.
1.2.5 immunohistochemical study
Adopt the SP method, the thick 4 μ m of paraffin section, routine dewaxes to water, behind the 3%H2O2 block endogenous property peroxidase, microwave antigen retrieval in sodium citrate solution, the sealing of 10% normal goats serum.Drip an anti-nephrin (1: 100), podocin (1: 120) and HPSE (1: 100)), 4 ℃ of refrigerator overnight.Drip the goat anti-rabbit igg working solution after PBS develops a film, hatch 20min for 37 ℃; Radix Cochleariae officinalis enzyme labelling strepto-avidin working solution is hatched 20min for 37 ℃; DAB colour developing is redyed, dehydration, transparent, mounting.Every example section picked at random 10 unduplicated glomerule visual field (* 400); Application of I mage Pro plus 6.0 softwares; Detect the AO and the area of positive signal in the glomerule; With the relative amount of positivity index (PI) expression positive material, computing formula is: PI=positive signal AO * positive signal area/glomerule area.
1.2.6RT-PCR research
Check in the mRNA nucleotide sequence of rat nephrin, podocin, HPSE and β-actin respectively by gene bank, the PCR primer is with the design of Primer Premier primer-design software, and is synthetic by Shanghai Sangon Biological Engineering Technology And Service Co., Ltd, sees table 2.
Table 2 rat nephrin, podocin, HPSE and β-actin primer sequence
Get renal cortex 25mg, after adding liquid nitrogen and grinding, extract test kit with total RNA from animal tissues and extract total RNA.The total RNA that extracts surveys the OD value with micro-ultraviolet-visible spectrophotometer: the OD260/OD280 value is between 1.8～2.0.Getting the total RNA of 1 μ g respectively is that reverse transcriptase is made reverse transcription reaction with M-MLV, and the cDNA product is stored in-20 ℃.Get 2 μ lcDNA as template, carry out pcr amplification with nephrin, podocin, HPSE and β-actin primer, reaction condition is: 94 ℃ of preparatory degeneration 3min; 94 ℃, 45s degeneration, (55 ℃ of nephrin, 53 ℃ of podocin; 53 ℃ of HPSE, 56 ℃ of β-actin) 45s annealing; 72 ℃, 60s extension circulate 35 times; 72 ℃ are extended 5min to 4 ℃.Get pcr amplification product 5 μ l electrophoresis in 1.2% agarose, uviol lamp is observed down, and Quantity One gel imaging system is taken a picture, and the amplified production electrophoretic band is carried out densitometric scan, measures electrophoretic band OD value (OD value).The relative expression quantity of nephrin, podocin, HPSE mRNA is represented with the OD value of nephrin, podocin, HPSE mRNA and the ratio of β-actin OD value.
2 statistical methods
Use the SPSS13.0 statistical software and carry out statistical analysis, with P＜0.05 difference for statistical significance is arranged.The statistical procedures measurement data is expression with
; Adopt variance analysis respectively to organize experimental result, each group relatively adopts minimum difference LSD method in twos.
3 experimental results
3.1 ordinary circumstance
Rats in normal control group diet, drinking-water situation, the mental status, daily routines are all normal.Diabetic nephropathy group rat polydipsia, polyphagia, polyuria symptom occur behind injection STZ 3d.Symptom is obvious when 2 weeks, and it is more remarkable to prolong above-mentioned symptom with the course of disease, and diabetic nephropathy group rat body weight alleviates during to 8 weeks, hair color is dull, lethargy.
3.2 respectively organize rat blood sugar
The rat blood sugar of respectively organizing after the modeling obviously raises, and blood glucose behind the bisbenzylisoquinoline alkaloid derivatives for treatment (BG) level descends, but does not recover normal fully.See table 3.
3.3 general index determining
24h urine protein (Pro; Mg/24h), 24h urinaryalbumin (ALB) is compared with model group; The 24h urine protein index of each group of bisbenzylisoquinoline alkaloid derivant is obviously improved; Difference has statistical significance, but does not reduce to the normal group level, and the 24h urine protein index difference between each group of bisbenzylisoquinoline alkaloid derivant also has statistical significance.See table 3 for details.
The influence
that table 3 Plumula Nelumbinis changes the general index of diabetic nephropathy rat
Annotate: compare with model group,
*P＜0.05,
*P＜0.01; With compared with normal,
#P＜0.05,
##P＜0.01; Compare P＜0.05, P＜0.05 with the captopril group
3.4HE dyeing light microscopic
Compare with normal group, model group shows as glomerular volume and increases the remarkable hypertrophy of mesangial cell; Hypertrophy in the basement membrane thickened, kidney small artery film, tube wall thickens; Glomerular capillary luminal stenosis, and visible part renal cells vacuolar degeneration, the sclerosis of minority glomerule had slight.And each group of bisbenzylisoquinoline alkaloid derivant is compared above-mentioned pathological change with the captopril group improvement is in various degree arranged with model group.
3.5 transmission electron microscope
The down visible normal rats podocyte structural integrity of transmission electron microscope, podocytic process is evenly distributed, and the slit membrane structure is clear.The model group podocyte has and comes off, podocytic process broadening, even merge, local slit diaphragm disappears, the broadening of basement membrane diffusivity.Each group of bisbenzylisoquinoline alkaloid derivant is compared above-mentioned pathological changes with the captopril group and is then alleviated to some extent with model group, show as slit membrane and recover, and basement membrane broadening alleviates, and wherein liensinine group, isoliensinine group and (-)-Neferine group are recovered near normal.Normal group renal cells clear in structure, organelles such as mitochondrion are high-visible; Model group renal cells nuclear chromatin is assembled, and it is empty that nuclear becomes, mitochondrial swelling in the kytoplasm; Wherein liensinine group, isoliensinine group and (-)-Neferine group are recovered near normal.
3.6 renal cortex nephrin mRNA, podocin mRNA, HPSE mRNA express
The expression of each group of bisbenzylisoquinoline alkaloid derivant, captopril group and normal rats nephridial tissue nephrin mRNA, podocin mRNA is significantly risen than model group, and difference has statistical significance.Each group of bisbenzylisoquinoline alkaloid derivant and normal rats nephridial tissue HPSE mRNA descend, and comparing difference with model group has statistical significance.Captopril group and model group be no difference of science of statistics relatively, sees table 4.
Table 4 kidney of rats is organized nephrin mRNA, podocin mRNA, HPSE mRNA relative expression quantity
Annotate: compare with model group,
*P＜0.05,
*P＜0.01; With compared with normal,
#P＜0.05,
##P＜0.01; Compare with the captopril group,
P＜0.05,
P＜0.05
3.7 kidney of rats podocyte counting, podocytic process width, podocytic process fusion rate and the influence of basement membrane average thickness
Each group of bisbenzylisoquinoline alkaloid derivant, captopril group and normal group and model group relatively have significant difference, see table 5.
Table 5 is respectively organized rat podocyte number, podocytic process width and fusion rate, base film thickness changes
Annotate: compare with model group,
*P＜0.05,
*P＜0.01; With compared with normal,
#P＜0.05,
##P＜0.01; Compare with the captopril group,
P＜0.05,
P＜0.05
Albuminuria is one of diabetic nephropathy clinical manifestation; Change as the 26S Proteasome Structure and Function of the GBM of glomerular filtration barrier structure main component and podocyte and slit diaphragm thereof; Wherein nephrin and its mechanical barrier of podocin albumen are closely related, and Heparan sulfate proteoglycan (HSPGs) electronegative electrostatic barrier when having formed glomerular filtration.Mechanical barrier and electrostatic barrier are the key factors that stops urine protein to spill.This experiment shows; The bisbenzylisoquinoline alkaloid derivant can reduce 24h urine protein and the 24h microdose urine protein of DN rat; Recover the podocyte number, reduce the podocytic process width, reduce fusion rate and reduce base film thickness; Its mechanism possibly be the expression through rise nephrin and podocin, the protein expression of downward modulation HPSE, thus the certain protection effect is played in glomerular filtration barrier (mechanical barrier and the electric screen barrier) damage of DN rat.
In sum; The bisbenzylisoquinoline alkaloid derivant of general formula I of the present invention thickens through alleviating glomerular basement membrane, reduces glomerular epithelium cell podocytic process and merges; Recover glomerule mechanical barrier and electrostatic barrier; Thereby reduce proteic spilling, diabetic nephropathy (III phase or IV phase) patient is had therapeutical effect preferably, can reduce 24h microalbumin (UAE) and 24h urine protein (UPQ); Albuminuria symptom to diabetic nephropathy has good inhibition effect, for the clinical treatment diabetic nephropathy provides new selection.
Claims (10)
1. described bisbenzylisoquinoline alkaloid derivant of general formula I or analog are treated the purposes in the diabetic nephropathy drugs in preparation:
General formula I
Wherein
R
1, R
2, R
3, R
4, R
5Be H, CH
3, CH
3CO, CH
3CH
2CO, CH
3CH
2CH
2CO;
Q
1, Q
2For-NH-,-NCH
3-, N → O ,-NR
+-.
2. purposes according to claim 1 is characterized in that: said medicine is that the treatment diabetic nephropathy III phase is or/and the medicine of IV phase.
3. purposes according to claim 1 and 2 is characterized in that: described medicine is to alleviate glomerular basement membrane to thicken, reduce the fusion of glomerular epithelium cell podocytic process or/and recover the medicine of glomerule mechanical barrier and electrostatic barrier.
4. purposes according to claim 1 and 2 is characterized in that: described medicine is the medicine of treatment proteinuria caused by diabetic nephropathy.
5. according to any described purposes of claim 1-4, it is characterized in that: Q
1, Q
2For-NCH
3-.
6. purposes according to claim 5 is characterized in that: R
1, R
2, R
3, R
4, R
5Be H or CH
3
7. purposes according to claim 6 is characterized in that: described bisbenzylisoquinoline alkaloid derivant or analog are:
8. according to any described purposes of claim 1-7; It is characterized in that: described medicine is to be active component by described bisbenzylisoquinoline alkaloid derivant of the general formula I of effective dose or analog, adds the preparation that acceptable accessories or complementary composition are prepared from.
9. purposes according to claim 8 is characterized in that: described preparation is oral formulations, ejection preparation.
10. purposes according to claim 9 is characterized in that: described preparation is tablet, oral liquid, pill, capsule, injection, unguentum, tincture, powder, electuary, suppository, cream, preparation capable of permeating skin or health food and food additive.
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Cited By (3)
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| CN105247038A (en) * | 2013-03-15 | 2016-01-13 | 小利兰·斯坦福大学托管委员会 | Benzylisoquinoline alkaloids (bia) producing microbes, and methods of making and using the same |
| US11859225B2 (en) | 2015-05-08 | 2024-01-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of producing epimerases and benzylisoquinoline alkaloids |
| US12018304B2 (en) | 2013-11-04 | 2024-06-25 | The Board Of Trustees Of The Leland Stanford Junior University | Benzylisoquinoline alkaloid (BIA) precursor producing microbes, and methods of making and using the same |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105247038A (en) * | 2013-03-15 | 2016-01-13 | 小利兰·斯坦福大学托管委员会 | Benzylisoquinoline alkaloids (bia) producing microbes, and methods of making and using the same |
| CN105247038B (en) * | 2013-03-15 | 2021-08-27 | 小利兰·斯坦福大学托管委员会 | Microorganisms that produce benzylisoquinoline alkaloids (BIAs) and methods of making and using the same |
| US12018304B2 (en) | 2013-11-04 | 2024-06-25 | The Board Of Trustees Of The Leland Stanford Junior University | Benzylisoquinoline alkaloid (BIA) precursor producing microbes, and methods of making and using the same |
| US11859225B2 (en) | 2015-05-08 | 2024-01-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of producing epimerases and benzylisoquinoline alkaloids |
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Application publication date: 20120912 |