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WO2023044365A1 - Utilisation de cyclodextrine pour améliorer la solubilité de substrats et augmenter l'efficacité de réaction de glycosylation enzymatique - Google Patents

Utilisation de cyclodextrine pour améliorer la solubilité de substrats et augmenter l'efficacité de réaction de glycosylation enzymatique Download PDF

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Publication number
WO2023044365A1
WO2023044365A1 PCT/US2022/076459 US2022076459W WO2023044365A1 WO 2023044365 A1 WO2023044365 A1 WO 2023044365A1 US 2022076459 W US2022076459 W US 2022076459W WO 2023044365 A1 WO2023044365 A1 WO 2023044365A1
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cyclodextrin
enzyme reaction
uridine diphosphate
substrate
reaction medium
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Yasmin-Pei Kamal CHAU
Jacob Donald Stanley WIRTH
Sheng Ding
Jing-ke WENG
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Doublerainbow Biosciences Inc
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Doublerainbow Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/18—Preparation of compounds containing saccharide radicals produced by the action of a glycosyl transferase, e.g. alpha-, beta- or gamma-cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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
    • C12N9/10—Transferases (2.)
    • 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
    • C12N9/10—Transferases (2.)
    • C12N9/1048—Glycosyltransferases (2.4)

Definitions

  • the method can include a) providing an aqueous reaction mixture; and b) allowing the reaction mixture to convert the substrate to a monosaccharide, a disaccharide, or an oligosaccharide of the substrate.
  • the aqueous reaction mixture can include: i) a substrate; ii) uridine diphosphate glycosyltransferases (UGT); iii) uridine diphosphate-monosaccharide; and iv) a cyclodextrin.
  • the uridine diphosphate-monosaccharide can be uridine diphosphate-glucose (“UDP -glucose”), uridine diphosphate-galactose (“UDP-galactose”), uridine diphosphatexylose (“UDP -xylose”), or uridine diphosphate-N-acetylglucosamine (“UDP-N- acetylglucosamine”).
  • UDP -glucose uridine diphosphate-glucose
  • UDP-galactose uridine diphosphate-galactose
  • UDP -xylose uridine diphosphatexylose
  • UDP-N- acetylglucosamine uridine diphosphate-N-acetylglucosamine
  • the substrate can be ivacaftor, enasidenib, or etoposide.
  • the cyclodextrin can be alpha-cyclodextrin, gamma-cyclodextrin, hydroxypropyl- beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin.
  • the concentration of the cyclodextrin can be at least about 1 mM, or from about 1 mM to about 150 mM.
  • the UGT can be immobilized in an affinity column in the presence of a cyclodextrin in the reaction media.
  • the method can include a) providing an aqueous reaction mixture and b) allowing the reaction mixture to convert the substrate to a monosaccharide, a disaccharide, or an oligosaccharide of the substrate.
  • the aqueous reaction mixture can include i) a substrate; ii) a yeast or bacteria that expresses a uridine diphosphate glycosyltransferases (UGT); iii) uridine diphosphatemonosaccharide; and iv) a cyclodextrin.
  • an enzyme reaction medium that can include: a) a buffer that maintains the medium at a pH from 6.5 to 8.0; b) from about 40 mM to about 60 mM of a salt selected from KC1 and NaCl; c) from about 200 mM to about 500 mM sucrose; d) from about ImM to about 2 mM UDP-glucose; e) from about 1 pM to about 2 pM of a uridine diphosphate glycosyltransferases (UGT); and f) from about 1 mM to about 150 mM of a cyclodextrin.
  • the buffer can be 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES) (e.g., approximately 50 mM of the HEPES).
  • HEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid
  • the enzyme reaction medium can further include a preservative, such as sodium azide (e.g., up to 0.02% (w/v) sodium azide).
  • the enzyme reaction medium can further include a yeast or bacteria that expresses a uridine diphosphate glycosyltransferases (UGT).
  • an enzyme reaction medium that can include a) a buffer that maintains the medium at a pH from 6.5 to 8.0; b) from about 40 mM to about 60 mM of a salt selected from KC1 and NaCl; c) from about 200 mM to about 500 mM sucrose; d) from about 1 pM to about2 pM of a uridine diphosphate glycosyltransferases (UGT); e) from about 0.1 pM to about 0.2 pM sucrose synthase; f) from about 0.5 mM to about 1 mM uridine diphosphate (UDP); g) from about 1 mM to about 150 mM of a cyclodextrin.
  • a buffer that maintains the medium at a pH from 6.5 to 8.0
  • the buffer can be 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES)
  • the enzyme reaction medium can further include a preservative, such as sodium azide (e.g., up to 0.02% (w/v) sodium azide).
  • a preservative such as sodium azide (e.g., up to 0.02% (w/v) sodium azide).
  • FIG. l is a bar graph showing that each drug tested shows different solubilities in different CDs in the enzyme reaction buffer, and these properties can only be determined through experimental screening. Error bars are the standard deviation of 3 replicates performed on separate days.
  • CD cyclodextrin
  • HP hydroxypropyl
  • SBE sulfobutylether
  • FIG. 2 is a bar graph showing that most drugs show a linear relationship between solubility and increasing CD concentration. Error bars are the range of two replicate assays performed on separate days.
  • CD cyclodextrin
  • HP hydroxypropyl
  • SBE sulfobutylether.
  • FIG. 3 is a bar graph showing that an optimal concentration of hydroxypropyl- beta-cyclodextrin (HPBCD) improves the glycosylation of the small molecule ivacaftor in an in vivo transformation reaction with yeast cultures expressing a UGT.
  • HPBCD hydroxypropyl- beta-cyclodextrin
  • the % glycosylated is calculated by dividing the total sum of the peak areas of all glycosides by the peak area of the starting aglycone concentration.
  • the glycosides quantified are ivacaftor monoglucoside and ivacaftor diglucoside.
  • FIG. 4 is a bar graph showing that HPBCD concentration affects the growth of yeast cultures expressing a UGT.
  • FIG. 5 is a bar graph showing that the presence of HPBCD promotes the addition of multiple sugar groups on the same substrate.
  • the fold increase in ivacaftor triglucoside was calculated by dividing the triglucoside peak area at the indicated HPBCD concentration by the triglucoside peak area at 0 mM HPBCD.
  • the amount of ivacaftor triglucoside in 0 mM HPBCD is set to 1. This data comes from an experiment similar to the one described above, with the following modifications: only 0-21.9 mM (0-3.2% w/v) HPBCD was tested, and samples were taken after 96 hours of incubation. [0022] FIG.
  • FIG. 6 is a bar graph showing that including the cyclodextrin HPBCD in a purified enzyme batch glycosylation reaction results in increased glycosylation of etoposide while not negatively affecting the enzyme activity.
  • Data shows representative results from one out of three replicate experiments. All three experiments showed the same general trends.
  • Each reaction contained 0.1 mg/mL etoposide as the sugar acceptor. At this concentration, etoposide is soluble in 0, 10, and 50 mM HPBCD.
  • the % glycosylated is calculated by dividing the total sum of the peak areas of all glycosides by the peak area of the starting aglycone concentration. In this experiment, the glycoside quantified is a single etoposide monoglucoside.
  • CDs Cyclodextrins
  • CDs Cyclodextrins
  • the most common CDs are composed of 6, 7, or 8 monosaccharide units called alpha-, beta-, and gamma-CDs, respectively.
  • Other types of CDs contain chemical modifications on the monosaccharide units, such as addition of a methyl group, hydroxypropyl group, sugar group, sulfate group, or other specialized chemical modification.
  • CDs form a toroidal three-dimensional structure with an external hydrophilic surface and an internal hydrophobic cavity. The cavity size and aqueous solubility of each CD depends on the composition of the monosaccharide units and any chemical modifications thereof.
  • Hydrophobic molecules can insert into the hydrophobic cyclodextrin cavity to form inclusion complexes.
  • the ability of a hydrophobic molecule to form a complex with a cyclodextrin is a function of compatibility in size, shape, and chemical interactions between the molecule and the cyclodextrin cavity.
  • CDs can interact with molecules of various sizes from small molecule therapeutics to peptides, lipids, and even proteins. 1 ’ 3 4 The most common application of CDs as solubility enhancers is in drug formulation development to enhance the bioavailability of pharmaceutical drugs. 5
  • CDs can also enhance substrate solubility in enzyme reactions.
  • Use of CDs as solubilizers in this context allows the enzyme reaction to proceed in a completely aqueous environment with minimal impact on enzyme activity. For example, glycosylation of lipids to form glycolipids in an aqueous buffer only occurred with the addition of gamma-cyclodextrin into the reaction buffer. 6
  • Addition of hydroxypropyl-beta-cyclodextrin (HPBCD) enhanced the solubility of styrene oxide, which enhanced the initial reaction rate of hydrolysis by epoxide hydrolase.
  • CDs have also been used to complex free fatty acids to enhance enzymatic reactions on those fatty acid substrates.
  • CD solubilize a molecule most efficiently.
  • different CDs solubilize different flavonoid molecules to different degrees.
  • gamma-cyclodextrin enhanced the solubility of lipid substrates and allowed glycosylation of these lipid substrates in an aqueous enzyme reaction.
  • alphacyclodextrin failed to solubilize the lipid substrates, and glycosylation in a fully aqueous enzyme reaction was not observed. 6
  • cyclodextrins are suitable, such as alpha-, beta-, or gammacyclodextrins substituted with one or more hydrophilic groups, such as monosaccharide (e.g., glucosyl, maltosyl), carboxyalkyl (e.g., carboxylmethyl, carboxyethyl), hydroxyalkyl- substituted (e.g., hydroxyethyl, 2-hydroxypropyl (sometimes referred to as simply hydroxypropyl)) and sulfoalkylether-substituted beta-cyclodextrin.
  • monosaccharide e.g., glucosyl, maltosyl
  • carboxyalkyl e.g., carboxylmethyl, carboxyethyl
  • hydroxyalkyl- substituted e.g., hydroxyethyl, 2-hydroxypropyl (sometimes referred to as simply hydroxypropyl)
  • Particularly suitable gamma- or beta-cyclodextrins include hydroxypropyl beta-cyclodextrin (HPBCD), hydroxypropyl gamma-cyclodextrin, and sulfobutylether beta-cyclodextrin (SBECD).
  • HPBCD hydroxypropyl beta-cyclodextrin
  • SBECD sulfobutylether beta-cyclodextrin
  • Substituted beta-cyclodextrins including: 6-O-glucosyl-beta-cyclodextrin, 6-O- maltosyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, carboxyethyl-beta- cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin.
  • Gamma-cyclodextrin and the following substitute gamma-cyclodextrins carboxymethyl-gamma-cyclodextrin, carboxyethyl-gamma-cyclodextrin, hydroxypropyl- gamma-cyclodextrin.
  • Particularly suitable cyclodextrins are hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, and sulfobutylether-beta-cyclodextrin.
  • cyclodextrins include randomly methylated cyclodextrin, succinyl-alpha- CD, succinyl-beta-CD, succinyl-hydroxypropyl-beta-CD, acetyl-beta-CD, triacetyl-beta-CD.
  • Preferred cyclodextrins include alpha-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, and sulfobutylether- beta-cyclodextrin.
  • a potential strategy for improving or modulating the efficacy, safety, and/or PK/PD profile of a small molecule therapeutics is modification by glycosylation.
  • the small molecule, or aglycone is modified by the addition of one or more sugar groups or chains of two or more sugar groups (called oligosaccharides) to nucleophilic centers of the aglycone.
  • oligosaccharides sugar groups or chains of two or more sugar groups
  • GTs Glycosyltransferases
  • UDP uridine diphosphate
  • glycosylation of small molecule are disclosed in international patent applications PCT/US2021/022416, PCT/US2021/022410, and PCT/US2021/022414, which disclose glycosylation of ivacaftor, enasidenib, and etoposide, respectively.
  • the sugar donor molecule is generally hydrophilic
  • the acceptor molecule for glycosylation may not be.
  • many therapeutic small molecules are characterized by limited aqueous solubility. It is estimated that -40% of new chemical entities exhibit low aqueous solubility (solubility ⁇ 10 pM or 5 pg/mL for a molecule with a molecular weight of 500). 17
  • a significant limitation to glycosylation reaction efficiency in aqueous environments is the limited aqueous solubility of the acceptor molecule.
  • Cyclodextrins present an easy and inexpensive solution to solubilize higher concentrations of acceptor molecules into aqueous enzyme reaction solutions. This will allow for the production of sufficient quantities of glycosylated product for preclinical research and development, clinical trials, and industrial-scale production.
  • Media for conducting the enzymatic reaction typically include a buffer, a salt, a stabilizing agent, UDP -glucose, a uridine diphosphate glycosyltransferases (UGT), and a cyclodextrin.
  • the buffer maintains the reaction medium at a pH from about 6.5 to about 8.0.
  • suitable buffers including 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES), Tris-HCl and phosphate buffer.
  • HEPES is used as a buffer, preferably at a concentration of about 50 mM.
  • the salt is sodium chloride (NaCl) or potassium chloride (KC1). In preferred embodiments, the salt is KC1.
  • the salt can be present at a concentration from about 40 mM to about 60 mM.
  • the stabilizing agent can be sucrose, glucose, and/or glycerol.
  • the stabilizing agent is sucrose.
  • the sucrose can be present at a concentration from about 200 mM to about 500 mM.
  • the sucrose is present at a concentration of about 300 mM.
  • UDP-glucose is present at a concentration from about ImM to about 2 mM.
  • the UGT is present at a concentration from about 1 pM to about 2 pM.
  • the cyclodextrin is present at a concentration from about 1 mM to about 150 mM.
  • enzyme reaction medium includes a preservative.
  • the preservative is sodium azide, preferably at a concentration up to about 0.02% (w/v), even more preferably at a concentration of about 0.01% (w/v).
  • the reaction media includes a sucrose synthase (SuSy) and UDP, but does not need to include UDP- glucose.
  • the reaction media includes a buffer, a salt, sucrose, a SuSy, UDP, a uridine diphosphate glycosyltransferases (UGT), and a cyclodextrin.
  • the buffer maintains the reaction medium at a pH from about 6.5 to about 8.0.
  • HEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid
  • Tris-HCl Tris-HCl
  • phosphate buffer Tris-HCl
  • HEPES 4-(2-hy droxy ethyl)- 1 -piperazineethanesulfonic acid
  • Tris-HCl Tris-HCl
  • phosphate buffer Tris-HCl
  • phosphate buffer preferably at a concentration of about 50 mM.
  • the salt is sodium chloride (NaCl) or potassium chloride (KC1). In preferred embodiments, the salt is KC1.
  • the salt can be present at a concentration from about 40 mM to about 60 mM.
  • the sucrose can be present at a concentration from about 200 mM to about 500 mM. Preferably, the sucrose is present at a concentration of about 300 mM.
  • the UGT is present at a concentration from about 1 pM to about 2 pM.
  • Sucrose synthase is present at a concentration from about 0.1 pM to about 0.2 pM.
  • UDP is present at a concentration from about 0.5 mM to about 1 mM.
  • the cyclodextrin is present at a concentration from about 1 mM to about 150 mM.
  • enzyme reaction medium includes a preservative.
  • the preservative is sodium azide, preferably at a concentration up to about 0.02%, even more preferably at a concentration of about 0.01%.
  • Each drug is soluble to different degrees with different CDs.
  • Some drugs e.g. etoposide
  • Some drugs e.g. ivacaftor, paclitaxel
  • Table 1 Data of FIG. 1.
  • CD concentrations ranged from 1.56 mM to 50 mM (approximately 0.2-8% w/v depending on the CD average molecular weight).
  • HPBCD (0-55 mM or 0-8% w/v) was added to selective yeast media (lx yeast nitrogen base (BioWorld), 2% w/v glucose). Then, ivacaftor was diluted from a DMSO drug stock to a final concentration of 0.2 mg/mL. The media was briefly vortexed to mix, and incubated at 30°C while shaking at 200 rpm for 30 minutes to allow the CD-drug complex to form. An overnight yeast culture was diluted into the media to a starting OD600 of 0.1 to start the reaction. The reaction was incubated for the indicated lengths of time.
  • HPBCD glycosylated ivacaftor
  • the glycosylation activity of the purified UGT DRB0458 (SEQ ID NO: 2) in the presence of no CD, a low concentration of CD (10 mM or 1.5% w/v), and a high concentration of CD (50 mM or 7.3% w/v) was compared.
  • the sugar acceptor molecule was etoposide and the sugar donor molecule, UDP-glucose, was regenerated using the enzyme sucrose synthase and sucrose.
  • UDP 0.5 mM
  • HPBCD 0.1%
  • etoposide 0.1 mg/mL
  • the UGT enzyme reaction buffer 50 mM HEPES pH 7.5, 50 mM KC1, 300 mM sucrose.
  • the solution was vortexed until clear.
  • etoposide is soluble in the buffer with no HPBCD and in buffer with 10 and 50 mM HPBCD.
  • the UGT DRB0458 (SEQ ID NO: 2); 2 pM
  • SuSy 0.2 pM
  • HPBCD Since the concentration of etoposide used in this experiment is already completely soluble in buffer without HPBCD and in buffer with 10 and 50 mM HPBCD, HPBCD likely promotes glycosylation by further stabilizing the etoposide in solution (precipitation is less likely to occur over time), stabilizing the UGT or SuSy enzymes, or stabilizing the enzyme-substrate complex.
  • Glycosyltransferases Structures, Functions, and Mechanisms. Annual Review of Biochemistry vol. 77 521-555 (2008).

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Abstract

L'invention concerne des procédés de glycosylation d'un substrat à l'aide d'uridine diphosphate glycosyltransférases (UGT) en combinaison avec de la cyclodextrine.
PCT/US2022/076459 2021-09-17 2022-09-15 Utilisation de cyclodextrine pour améliorer la solubilité de substrats et augmenter l'efficacité de réaction de glycosylation enzymatique Ceased WO2023044365A1 (fr)

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US20200308617A1 (en) * 2013-02-06 2020-10-01 Evolva Sa Methods for improved production of rebaudioside d and rebaudioside m
US20210095317A1 (en) * 2014-12-12 2021-04-01 University Of Copenhagen N-Glycosylation
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WO2021188459A1 (fr) * 2020-03-16 2021-09-23 Doublerainbow Biosciences Inc. Glycosides ivacaftor, leurs procédés de fabrication et leurs utilisations dans le traitement de la fibrose kystique
WO2021188456A1 (fr) * 2020-03-16 2021-09-23 Doublerainbow Biosciences Inc. Glycosides d'enasidenib et procédés de traitement de maladies associées à un dysfonctionnement de l'isocitrate déshydrogénase (idh)
WO2021188457A1 (fr) * 2020-03-16 2021-09-23 Doublerainbow Biosciences Inc. Glycosides d'étoposide, leurs procédés de fabrication et leurs utilisations en tant que médicament anticancéreux

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