WO2011110049A1 - Polypeptide de fusion anti-vih et son utilisation - Google Patents
Polypeptide de fusion anti-vih et son utilisation Download PDFInfo
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- WO2011110049A1 WO2011110049A1 PCT/CN2011/000333 CN2011000333W WO2011110049A1 WO 2011110049 A1 WO2011110049 A1 WO 2011110049A1 CN 2011000333 W CN2011000333 W CN 2011000333W WO 2011110049 A1 WO2011110049 A1 WO 2011110049A1
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- 0 Cc1cc(*)c(C)[n]1-c(cc1)cc(O)c1C(O)=O Chemical compound Cc1cc(*)c(C)[n]1-c(cc1)cc(O)c1C(O)=O 0.000 description 5
- YALZTLMQKUQEEK-UHFFFAOYSA-N Cc1cc(Br)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl Chemical compound Cc1cc(Br)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl YALZTLMQKUQEEK-UHFFFAOYSA-N 0.000 description 1
- VWDVBXDJMJVEJW-UHFFFAOYSA-N Cc1cc(CO)c(C)[n]1-c(cc1)cc(O)c1C(O)=O Chemical compound Cc1cc(CO)c(C)[n]1-c(cc1)cc(O)c1C(O)=O VWDVBXDJMJVEJW-UHFFFAOYSA-N 0.000 description 1
- SBLFKENQSIFISX-UHFFFAOYSA-N Cc1cc(Cl)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl Chemical compound Cc1cc(Cl)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl SBLFKENQSIFISX-UHFFFAOYSA-N 0.000 description 1
- FCDGRCAGCXSNFW-UHFFFAOYSA-N Cc1cc(F)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl Chemical compound Cc1cc(F)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl FCDGRCAGCXSNFW-UHFFFAOYSA-N 0.000 description 1
- WIUFPRAQTCXWNT-UHFFFAOYSA-N Cc1cc(I)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl Chemical compound Cc1cc(I)c(C)[n]1-c(cc1)cc(C(O)=O)c1Cl WIUFPRAQTCXWNT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0006—Oxidoreductases (1.) acting on CH-OH groups as donors (1.1)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Definitions
- the invention belongs to the field of biomedicine and relates to a polypeptide for inhibiting HIV infection and a use thereof. Specifically, it relates to a polypeptide having a HIV-1 transmembrane glycoprotein subunit (gp41) as a target and having an activity of inhibiting HIV infection.
- the present invention also relates to a pharmaceutical composition containing the polypeptide, and the use of the polypeptide for the preparation of a medicament for treating or preventing acquired immunodeficiency syndrome (AIDS, AIDS) and a disease caused by HIV infection, or an HIV fusion inhibitor.
- AIDS acquired immunodeficiency syndrome
- AIDS acquired immunodeficiency syndrome
- the HIV-1 envelope glycoprotein (Env) is a functional protein on the surface of the virus that mediates fusion between the viral membrane and the host cell membrane, allowing HIV-1 to enter the target cell.
- Env is composed of a surface subunit (gpl 20) and a transmembrane subunit (gp41), wherein the surface subunit gpl 20 is responsible for recognizing and binding to a specific receptor of the host cell, and the transmembrane subunit gp41 is responsible for mediating membrane fusion.
- the Gp41 molecule consists of three parts: the cytoplasmic region, the transmembrane region, and the extracellular region.
- the extracellular region contains three important functional regions involved in membrane fusion: fusion peptide (FP), N-terminal repeat (N-termina l Heptad repeat, NHR, also known as HR1) and C-terminal repeat (CHR, also known as HR2).
- FP fusion peptide
- NHR N-termina l Heptad repeat
- CHR C-terminal repeat
- gpl 20 In the process of HIV infection of target cells, gpl 20 binds to the target cell surface CD4 receptor and chemokine co-receptor (CCR5 or CXCR4), causing structural rearrangement of gp41, and the N-terminal fusion peptide is inserted into the host cell membrane.
- the NHR then interacts with the CHR to form a stable hexa-helix bundle (6-HB).
- 6-HB stable hexa-helix bundle
- three NHR helices interact to form a centrally located helical trimer, while three CHR helices are combined in an antiparallel manner in a highly conserved hydrophobic groove formed by three N-helix surfaces. 1998, 93: 681-684).
- NHR residues (res idues aa: 565-581), which play a key role in membrane fusion and maintaining 6-HB stability, and are important targets for drug action.
- Intramolecular folding of GP41 to form 6-HR results in the viral membrane approaching the target cell membrane to a suitable location, ultimately resulting in fusion of the two, N Engl J Med 2003, 348: 2228-33).
- Any compound that inhibits the binding of HR and CHR prevents the formation of the 6-HB structure in the HIV gp41 molecule, prevents the fusion of the viral membrane and the target cell membrane, thereby preventing the virus from entering the target cell and protecting the immune cells from infection.
- C-peptides Synthetic polypeptides derived from gp41 CHR (called C-peptides), such as C34 and T-20, have excellent inhibition of HIV fusion activity. They bind to NHR and occupy the site of action of CHR itself, thereby inhibiting its own CHR. The formation of a 6-HB structure with NHR interrupts the membrane fusion process, and the fusion cannot be completed to achieve antiviral effects (Cell, 1997, Vo. 89, 263-273).
- the first C-peptide HIV fusion inhibitor T-20 (common name: Enfuv i r t ide, trade name: Fuzeon) was approved by the US FDA in March 2003.
- the fusion peptide (FP) located at the N-terminus of the gp41 protein is a highly hydrophobic functional region consisting of approximately 23 amino acid residues, which plays a key role in the fusion of the HIV-1 envelope with the host cell membrane. Similarly, it is also an effective target for fusion inhibitors.
- the present inventors obtained a polypeptide by creative labor and a large amount of experiments, and surprisingly found that the polypeptide is effective for inhibiting HIV infection activity, particularly, inhibiting HIV-1 infection activity.
- the following invention is thus provided:
- One aspect of the invention relates to a polypeptide of formula (I), a stereoisomer thereof, or a physiologically toxic salt thereof,
- HSD represents a structural region, which is a cc-helical polypeptide having a stable three-dimensional structure, and is capable of forming a Hessoid structure with HIV-1 gp41 NHR;
- FD ⁇ FD 2 , FD 3 represent a functional region, wherein FD 1 5 FD 2 is a peptide chain or a small molecule compound which is linked to HSD such that the polypeptide produces or enhances the activity of inhibiting HIV infection, and FD 2 may be the same or different, and ? 0 and? 0 2 at least one; FD 3 is a polypeptide fragment capable of binding to the HIV-1 gp41 fusion peptide region (FP), and FD 3 is necessary;
- l inker, l inker 2 and l inker 3 represent the connecting arm connecting the structure area and the functional area.
- l inker l inker 2 and 1 inker 3 may exist at least one or none of them, and the three connecting arms are mutually Can be the same or different;
- the structural region, the functional region, and the linking arms are connected end to end by an amide bond or an ester bond;
- the HSD is a gp41 protein CHR homologous sequence or a mutant thereof, or an artificially designed peptide sequence having a helical structure.
- the HSD is a structure selected from the group consisting of: YTSLIHSLIEESQNQQEKNEQELLELDK and mutants thereof, or fragments and mutants thereof, or the structure shown in the following formula:
- A is selected from: D-type or L-form Glu or Asp, D-type or L-type Ser or Thr, or D-type or L-type unnatural amino acid having proton donor properties;
- B is selected from: D-type or L-form Lys or Arg or His, D-type or L-type Gin or Asn, or D-type or L-type unnatural amino acid having proton acceptor properties;
- X dl , X d2 , X d3 , X d4 are selected from the group consisting of: Tyr, Phe, Trp, Nal, Leu, VaK Gin,
- X el , X e2 , X e3 , X e4 are selected from: Leu, Gln, Ile, Thr, Dsp, Met, Ala,
- n is an integer from 1 to 6. Specifically, n is 1, 2, 3, 4, 5, or 6.
- the HSD is a structure selected from the group consisting of:
- KKLIEEI (AKKLAEE) n
- AKKLAEE (AKKLAEE) n
- IKKLAEE (IKKLAEE) n
- n is an integer from 1 to 6 (for example, n is 1, 2, 3, 4, 5, or 6); or is a structure selected from the group consisting of: SEQ ID NO: 39-88
- the FDi, FD 2 is a knot selected from the group consisting of
- SM2 wherein, in SMI, SM2, X is -CH 2 -, -CO-, - 0-, NH -, - S -, F, Cl, Br, or I; Y is - H, -0H, -C00H, - NH 2 -, -SH, - CH 2 F- CH 2 C1, -CH 2 Br, or -CH 2 I, n is an integer from 0 -6 (for example, n is 0, 1, 2, 3, 4, 5, Or 6);
- FDi is a structure (SM1001-SM1020) selected from the group consisting of -C00H on the benzene ring and -0H or -NH 2 of the linker 1 or HSD
- FD 2 is selected from a structure (SM2001 - SM2020), on the phenyl ring by FD 2 - C00H or 1 inker 3 and the FD 3 - 0H or - NH connection:
- the FD 1 and FD 2 are selected from the group consisting of SEQ ID NO: 114-116
- the FD 3 is a gp41 protein FP region polypeptide sequence and a fragment thereof or a derivative of the peptide sequence LEAIPMS IPPEVKFNKPFVFLM or a derivative thereof or a fragment thereof or a fragment thereof,
- the FD 3 is a structure selected from the group consisting of the following sequences of SEQ ID NO: 117-122:
- the l inker l, l inker 2 and l inker 3 are structures selected from the group consisting of:
- the l inkerl, l inker 2 and l inker 3 are structures selected from the group consisting of:
- the formula (I) is the SEQ ID NO: 1-38 polypeptide shown in Table 1 below:
- X is 6-aminocaproic acid; and a plurality of 6-aminocaproic acid are linked to each other by an amide bond, and in the sequence listing, 6-aminohexanoic acid is represented by Xaa.
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising the above A peptide, a stereoisomer thereof, or a physiologically inferior salt thereof, and a pharmaceutically acceptable carrier and excipient.
- a further aspect of the invention relates to the above polypeptide, a stereoisomer thereof, or a non-physiologically toxic salt thereof, in the preparation of a medicament for treating or preventing acquired immunodeficiency syndrome and a disease caused by HIV infection, or an HIV fusion inhibitor use.
- a further aspect of the invention relates to a method of treating or preventing acquired immunodeficiency syndrome and a disease caused by HIV infection comprising administering an effective amount of a polypeptide of the invention, a stereoisomer thereof, or a physiologically toxic salt thereof step.
- the dosage of the polypeptide of the present invention, its stereoisomer, or its non-physiologically toxic salt depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight and individual response of the patient or animal, The specific compound used, the route of administration, the number of administrations, and the like.
- the above dosages may be administered in a single dosage form or divided into several, for example two, three, four dosage forms.
- the term "polypeptide” includes not only polypeptides generally referred to in the art, but also derivatives of polypeptides, including the polypeptides defined by the following formula (I).
- a polypeptide is also referred to as a peptide or a peptide chain.
- the term "its stereoisomer” means its corresponding D- or L-stereo configuration.
- Env envelope glycoprotein envelope glycoprotein
- Glu Glutamic acid, E) glutamic acid HBTU 2-(1 ⁇ -1-hydroxybenzotriazole)-1, 1, 3, 3-tetradecylurea hexafluorophosphate His(Histidine, H) Histidine HoBt (1-Hydroxylbenzotriazole anhydrous) 1-phenylbenzotriazole
- HIV Human Immunodeficiency Virus
- HIV-1 Human Immunodeficiency Virus Type I
- Lys (Lys ine, K) lysine MALDI-TOF-MS matrix-assisted laser desorption time-of-flight mass spectrometry Nal naphthylalanine NHR ( N- termina l heptad repeat ) N-terminal repeat
- Trp Tryptophan
- a portion of the polypeptide of the present invention can affinity with the HR1 region to inhibit 6-HB formation; a portion can bind to the FP region, anchoring the inhibitor molecule to the host cell membrane, thereby increasing the local inhibitor concentration near the membrane.
- the polypeptide of the present invention is effective in inhibiting HIV infection, particularly the biological activity of HIV-1. detailed description
- the solid phase synthesis carrier MBHA resin used in the examples is Tianjin Nankai Synthetic Co., Ltd.; DCC, H0BT, HBTU, DIEA and Fmoc protected natural amino acids or D-type unnatural amino acids are Shanghai Jill Biochemical Co., Ltd. and Chengdu Chengnuo New Technology Co., Ltd. responsible company products. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially.
- Example 1 Synthesis of polypeptide SEQ ID NO: 1
- Rink Amid resin (0.50mmol) as the solid phase carrier, DCC/HOBt or HBTU/DIEA as the condensing agent, according to the amino acid sequence of the polypeptide, from the C-terminus to the N-terminus, according to the standard Fmoc solid phase peptide synthesis method (Reference) Literature: Huang Weide, Chen Changqing, Peptide Synthesis, Science Press, 1985) Operational synthesis of Ac-lipids.
- the above peptide resin was placed in a 250 ml eggplant-shaped glass reaction flask, and 10 ml of the lysate I was added under a water bath.
- the lysate I formula: TFA: anisole: m-phenol: ethanedithiol: water 7.5: 1: 0.5 : 0.5: 0.5, stirring in ice bath for 30 min, stirring to room temperature, stirring for 90 min, adding 100 ml of cold anhydrous ether, suctioning to obtain white solid, adding water and dissolving in a suitable amount, suction filtration, and lyophilizing the filtrate to obtain white dry powder 0.47 g, RP- Purified by HPLC to obtain a pure product.
- MALDI-TOF-MS 5226.5 (theoretical value 5226.9).
- polypeptide of SEQ ID NO: 2-12, 16-38 was synthesized in accordance with the method of Example 1, except that the corresponding amino acid residues were transformed.
- Example 2 Polypeptide Synthesis of SEQ ID NO: 13
- MBHA resin (0.48mraol) as the solid phase carrier, DCC/HOBt or HBTU/DIEA as the condensing agent, according to the amino acid sequence of the polypeptide, from the C-terminus to the N-terminus, according to the standard Fmoc solid phase peptide synthesis method (Reference) : Huang Weide, Chen Changqing, Peptide Synthesis, Science Press, 1985) Operational Synthesis YTSLIHSLIEESQNQQEKNEQELLELDKWAS LWN FSIPPEVKFNKPFVFLM
- the above peptide resin was placed in a reactor of a HF cutter, and 1.0 mL of anisole was added. After the assembly, the system of the HF cutter was evacuated, and the reactor was cooled with liquid nitrogen. lOmL liquid HF was reacted at 0 ° C for 40 minutes. The HF was pumped off with an oil pump, the reactor was removed, solidified by adding anhydrous ethyl ether, and the suspension was transferred to a sand core funnel. It was washed three times with a small amount of cooled anhydrous diethyl ether, washed with an aqueous solution until the resin no longer adhered to each other, and the washing liquid was collected, and lyophilized to obtain a white dry powder. Purified by RP-HPLC. MALDI-TOF-MS: 6367.8 (theoretical value 6367.2).
- polypeptide of SEQ ID NO: 14-15 was synthesized by the method of Example 2, except that the corresponding amino acid residues were substituted.
- Example 3 Inhibition of HIV-1 biological activity
- polypeptides SEQ ID NO: 1 - 38 and control samples T20 and 4HRa-LBD were tested for their biological activity against HIV-1.
- sequences of T20 and 4HRa-LBD are as follows:
- T20 YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF (SEQ ID NO: 123);
- HIV-1 ⁇ infected ⁇ 9 cells H9/HIV-1 ready IB
- fluorescent reagent Calcein-AM Molecular Probes, Inc., Eugene, OR
- Test peptides from 25 ⁇ g / ml concentration twice gradient
- Fusion and unfused Calcein-labeled HIV-1 infected cells were counted using a reverse fluorescence microscope (Zeiss, Germany). IC 5 values were calculated.
- XTT assay and ELISA assay for C-peptide inhibition of HIV-1 replication activity MT-2 Cells were infected with HIV-1 IB overnight with or without test C peptide, and the peptide was diluted from 25 (mg/ml concentration twice. After four days of infection, the medium was collected overnight and p24 was detected by ELISA. Antigen. On day 6 of infection, cytopathic effect (CPE) was measured by addition of XTT tetrazolium salt staining indicator (PolySciencies, Inc., Warrington, PA).
- CPE cytopathic effect
- Sandwich ELISA method to detect C peptide inhibition of gp416-HB formation activity The test polypeptide was diluted from 25 (mg/ml concentration twice gradient. N36 peptide (2 ⁇ ) was mixed with the sample to be tested, pre-incubated at 37 ° C for 30 min, then added C34 ( 2 ⁇ ), incubated at 37 ° C for 30 min, then added to a closed ELISA plate (Costar, Corning Inc., Corning, NY), incubated at 37 ° C for 1 h; sequentially added 6-HB specific single. The cloned antibody NC-1, biotinylated IgG, SA-HRP, TMB was detected. Absorbance values at 450 nm (reference 570 nm) were measured. IC 5 values were calculated.
- the polypeptide of the present invention is effective in inhibiting HIV infection, particularly the biological activity of HIV-1.
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Abstract
Le polypeptide de fusion anti-VIH selon l'invention répond à la formule FD1-lieur1-HSD-lieur2-FD2-lieur3-FD3. Dans la formule, HSD est une répétition heptapeptidique (HR) ou d'un analogue de celui-ci ; FD1, FD2 et FD3 sont indépendamment choisis parmi un peptide inhibiteur du virus (VIRIP), un carboxyphénylpyrrole et des analogues de celui-ci, ou sont absents ; et lieur1, lieur2 et lieur3 sont indépendamment des lieurs pour la fusion, ou sont absents. Une composition pharmaceutique dudit polypeptide et son utilisation anti-VIH sont également décrites.
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CN201010123108 | 2010-03-12 | ||
CN201010123108.1 | 2010-03-12 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013075594A1 (fr) * | 2011-11-21 | 2013-05-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptide anti-infection par le vih conçu artificiellement, composition et utilisation associées |
WO2013075606A1 (fr) * | 2011-11-21 | 2013-05-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Conjugué petite molécule-polypeptide inhibant une infection par le vih |
CN103483428A (zh) * | 2012-06-11 | 2014-01-01 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
IL277528A (en) * | 2020-09-22 | 2022-04-01 | Ag Plenus Ltd | Herbicides and methods for their use |
Citations (1)
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CN1968964A (zh) * | 2004-06-18 | 2007-05-23 | Ipf医药有限公司 | 寡聚肽及其治疗hiv感染的用途 |
-
2011
- 2011-03-02 WO PCT/CN2011/000333 patent/WO2011110049A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1968964A (zh) * | 2004-06-18 | 2007-05-23 | Ipf医药有限公司 | 寡聚肽及其治疗hiv感染的用途 |
Non-Patent Citations (1)
Title |
---|
PAN, C. ET AL.: "HIV-1 gp41 Fusion Intermediate: A Target for HIV Therapeutics.", J FORMOS MED ASSOC., vol. 109, no. 2, February 2010 (2010-02-01), pages 94 - 105, XP026938502, DOI: doi:10.1016/S0929-6646(10)60029-0 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013075594A1 (fr) * | 2011-11-21 | 2013-05-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Polypeptide anti-infection par le vih conçu artificiellement, composition et utilisation associées |
WO2013075606A1 (fr) * | 2011-11-21 | 2013-05-30 | 中国人民解放军军事医学科学院毒物药物研究所 | Conjugué petite molécule-polypeptide inhibant une infection par le vih |
CN103483428A (zh) * | 2012-06-11 | 2014-01-01 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子-多肽缀合物 |
CN103483428B (zh) * | 2012-06-11 | 2017-05-17 | 中国人民解放军军事医学科学院毒物药物研究所 | 抑制hiv感染的小分子‑多肽缀合物 |
IL277528A (en) * | 2020-09-22 | 2022-04-01 | Ag Plenus Ltd | Herbicides and methods for their use |
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