- Aldehyde capture ligation for synthesis of native peptide bonds
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Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, we introduce an aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies.
- Raj, Monika,Wu, Huabin,Blosser, Sarah L.,Vittoria, Marc A.,Arora, Paramjit S.
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Read Online
- Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates
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Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.
- Hu, Xinyue,Jiang, Hailun,Bai, Weiqi,Liu, Xiujun,Miao, Qingfang,Wang, Linlin,Jin, Jie,Cui, Along,Liu, Rui,Li, Zhuorong
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- Isostearyl Mixed Anhydrides for the Preparation of N-Methylated Peptides Using C-Terminally Unprotected N-Methylamino Acids
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Sustainable and efficient manufacturing methods for N-methylated peptides remain underexplored despite growing interest in therapeutic N-methylated peptides within the pharmaceutical industry. A methodology for the coupling of C-terminally unprotected N-methylamino acids mediated by an isostearic acid halide (ISTAX) and silylating reagent has been developed. This approach allows for the coupling of a wide variety of amino acids and peptides in high yields under mild conditions without the need for a C-terminal deprotection step in the process of C-terminal elongation. These advantages make this a useful synthetic method for the production of peptide therapeutics and diagnostics containing N-methylamino acids.
- Cary, Douglas R.,Handa, Michiharu,Kobayashi, Yutaka,Kurasaki, Haruaki,Masuya, Keiichi,Matsuda, Ayumu,Matsumoto, Masatoshi,Morimoto, Koki,Nagaya, Akihiro,Nishizawa, Naoki,Taguri, Tomonori,Takeuchi, Hisayuki
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Read Online
- Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity
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In order to realize the targeted delivery of paclitaxel (PTX) to tumor through an environment-sensitive mechanism, increase its solubility in water and reformulate without toxic excipients, a novel PTX conjugate, PEG-VC-PABC-PTX was designed and synthesiz
- Liang, Liang,Lin, Song-Wen,Dai, Wenbing,Lu, Jing-Kai,Yang, Ting-Yuan,Xiang, Yu,Zhang, Yang,Li, Run-Tao,Zhang, Qiang
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- Hydrogelation and self-assembly of Fmoc-tripeptides: Unexpected influence of sequence on self-assembled fibril structure, and hydrogel modulus and anisotropy
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The self-assembly and hydrogelation properties of two Fmoc-tripeptides [Fmoc = N-(fluorenyl-9-methoxycarbonyl)] are investigated, in borate buffer and other basic solutions. A remarkable difference in self-assembly properties is observed comparing Fmoc-VLK(Boc) with Fmoc-K(Boc)LV, both containing K protected by Nε-tert-butyloxycarbonate (Boc). In borate buffer, the former peptide forms highly anisotropic fibrils which show local alignment, and the hydrogels show flow-aligning properties. In contrast, Fmoc-K(Boc)LV forms highly branched fibrils that produce isotropic hydrogels with a much higher modulus (G′ > 104 Pa), and lower concentration for hydrogel formation. The distinct self-assembled structures are ascribed to conformational differences, as revealed by secondary structure probes (CD, FTIR, Raman spectroscopy) and X-ray diffraction. Fmoc-VLK(Boc) forms well-defined β-sheets with a cross-β X-ray diffraction pattern, whereas Fmoc-KLV(Boc) forms unoriented assemblies with multiple stacked sheets. Interchange of the K and V residues when inverting the tripeptide sequence thus leads to substantial differences in self-assembled structures, suggesting a promising approach to control hydrogel properties.
- Cheng,Castelletto,Moulton,Newby,Hamley
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Read Online
- Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing
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Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such
- Widdison, Wayne C.,Ponte, Jose F.,Coccia, Jennifer A.,Lanieri, Leanne,Setiady, Yulius,Dong, Ling,Skaletskaya, Anna,Hong, E. Erica,Wu, Rui,Qiu, Qifeng,Singh, Rajeeva,Salomon, Paulin,Fishkin, Nathan,Harris, Luke,Maloney, Erin K.,Kovtun, Yelena,Veale, Karen,Wilhelm, Sharon D.,Audette, Charlene A.,Costoplus, Juliet A.,Chari, Ravi V. J.
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Read Online
- Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
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Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus-responsive and site-specific cleavage of DNA. However, the limitations of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. Inspired by the cathepsin B-sensitive dipeptide linkers in antibody–drug conjugates (ADCs) such as Adcetris, we have developed Val-Ala-02 and Val-Ala-Chalcone phosphoramidites for the automated synthesis of enzyme-cleavable oligonucleotides. Cathepsin B digests Val-Ala-02 and Val-Ala-Chalcone linkers efficiently, enabling cleavage of oligonucleotides into two components or release of small-molecule payloads. Based on the prior success of dipeptide linkers in ADCs, we believe that these dipeptide linker phosphoramidites will promote new clinical applications of therapeutic oligonucleotides.
- Jin, Cheng,EI-Sagheer, Afaf H.,Li, Siqi,Vallis, Katherine A.,Tan, Weihong,Brown, Tom
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supporting information
(2022/02/17)
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- A Wireframe DNA Cube: Antibody Conjugate for Targeted Delivery of Multiple Copies of Monomethyl Auristatin E
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In recent years, several antibody drug conjugates (ADC) have been accepted by the FDA as therapeutics against cancer. It is well-known that control of drug-to-antibody ratio (DAR) is vital for the success of an ADC, which inspires the advancement of bette
- M?rcher, Anders,Nijenhuis, Minke A. D.,Gothelf, Kurt V.
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supporting information
p. 21691 - 21696
(2021/09/02)
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- ANTIBODY-DRUG CONJUGATE
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Provided herein is an antibody-drug conjugate (ADC) especially a PEGylated mono or bispecific antibody-drug conjugate (BsADC) prepared with site-specific conjugation to provide homogeneous conjugate with high potency and low toxicity. It also relates to a
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Page/Page column 55-56; 58-59
(2021/10/22)
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- Linker, Antibody-Drug Conjugate Including Same and Use Thereof
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Provided are a linker represented by Formula I or I′, an antibody-drug conjugate containing the same, and use of thereof, a pharmaceutical composition comprising the antibody-drug conjugate, and use of the antibody-drug conjugate for treating and/or preventing a disease.
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Paragraph 0454-0456
(2021/08/27)
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- COMPOUNDS, COMPOSITIONS, METHODS, AND USES FOR TREATING CANCER AND IMMUNOLOGICAL DISORDERS
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The present disclosure provides novel polypeptide-therapeutic compound or hormone-therapeutic compound conjugates using cleavable or non-cleavable linkers, whereby the polypeptide or hormone serves to target specific cells using receptor expression on the targeted cell to bind the ligand (polypeptide or hormone) carrying the therapeutic compound unlike antibody drug conjugates. Upon binding, the ligand and the therapeutic compound (multiples of the therapeutic compound in some embodiments) enter the cell by receptor-mediated endocytosis, and release drugs conjugated to the ligand by linkers, to interact with intracellular components to enhance, restore, or block a signal transduction process. The ligands for the polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: cytokines, growth factors and hormones among other proteins with corresponding cell surface specific receptors. The disorders targeted by such polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: immunological disorders (e.g., allergy and autoimmune disorders) and cancer.
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Paragraph 0546; 0551; 0553-0554
(2020/02/06)
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- Site-Specific Incorporation of Multiple Thioamide Substitutions into a Peptide Backbone via Solid Phase Peptide Synthesis
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Among various peptide modification strategies, thioamide substitution by replacing the carbonyl oxygen atom of an amide bond with a sulfur atom constitutes an invaluable tool for chemical biology, for use in peptide drug discovery and protein structure-fu
- Yang, Jinhua,Wang, Changliu,Yao, Chaochao,Chen, Chunqiu,Hu, Yafang,He, Guifeng,Zhao, Junfeng
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p. 1484 - 1494
(2020/01/02)
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- PROCESS FOR THE PREPARATION OF DRUG LINKER COMPOUNDS
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This disclosure generally relates to novel processes for the preparation of drug linker compounds and compositions comprising such drug linker compounds. The presently disclosed methods for synthesizing Fmoc-Val-Cit-PABOH and related compounds have also been found to minimize formation of diastereomeric impurities.
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Paragraph 0111-0112
(2019/06/17)
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- Unnatural amanitin type antibody conjugate
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The invention discloses unnatural amanitin type antibody conjugate. An unnatural amanitin as toxic as natural amanitins is conjugated with a biomolecule, which may combine with a target, through a bio-pharmaceutically acceptable connection structure so as to obtain a compound which is stable in plasma and which can effectively kill tumor cells in cells.
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Paragraph 0113; 0130; 0131; 0132
(2019/01/23)
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- An antibody-coupled drug targeting on EGFR, a preparation method thereof, and uses thereof
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The invention discloses an antibody coupling drug targeting on EGFR, a preparation method thereof and uses thereof. The antibody-conjugated drug targeting EGFR is named LR004-VC-MMAE consisting of anantibody, a cytotoxic drug and a linker, wherein the antibody drug conjugate has a structure represented by the formula I, wherein mAb is an LR004 monoclonal antibody, n=2-8. The novel antibody-conjugated drug LR004-VC-MMAE can not only target EGFR antigen, but also has strong cytotoxicity to tumor cells. Compared with LR004 itself, it did not affect the affinity, endocytosis and targeting of theantibody, and better retained its biological function. Compared to LR004, the antitumor effect of LR004-VC-MMAE antibody-conjugated drug is significantly improved, and the tumor disappeared. Comparedto LR004, LR004-VC-MMAE antibody-conjugated total antibody showed longer half-life, slower clearance rate, lower concentration of free MMAE in plasma, shorter half-life and faster clearance rate, which is conducive to reduce toxicity.
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Paragraph 0051; 0063; 0064; 0065
(2019/01/24)
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- Ynamide-Mediated Thiopeptide Synthesis
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Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH2, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.
- Yang, Jinhua,Wang, Changliu,Xu, Silin,Zhao, Junfeng
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supporting information
p. 1382 - 1386
(2019/01/08)
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- Dual-sensitivity polymer-medicine connective and preparation method and application thereof
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The invention discloses a dual-sensitivity polymer-medicine connective and a preparation method and application thereof, and belongs to the fields of polymer chemistry and a pharmaceutical preparation. The method comprises the steps of preparing an enzyme sensitivity substrate into an enzyme sensitivity substrate intermediate; enabling medicines and cystamine dihydrochloride to be prepared into amedicine derivative containing disulfide bonds; enabling the enzyme sensitivity substrate and the medicine derivative to be connected to prepare a dual-sensitivity medicine derivative; and finally, condensing the methoxypolyethylene glycols and the medicine derivative to obtain the dual-sensitivity polymer-medicine connective being sensitive to glutathione reduction and tissue protease B. The dual-sensitivity polymer-medicine connective can be self-assembled to amphiphilic polymer micelle, connecting bonds are disulfide bonds and dipeptide, and the dual-sensitivity polymer-medicine connectivecan realize responsiveness crack at the tumor parts to release medicines. The invention further discloses the preparation method of an mPEG-VC-SS-GA copolymer and an application of the mPEG-VC-SS-GA copolymer as an antitumor medicine carrier.
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Paragraph 0054; 0057; 0058
(2020/01/08)
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- PEPTIDIC LINKERS AND CRYPTOPHYCIN CONJUGATES, USEFUL IN THERAPY, AND THEIR PREPARATION
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The present disclosure relates to compounds of formula (I): RCG1-L-P (I) wherein RCG1 represents a reactive chemical group being reactive towards a chemical group present on a polypeptide such as an antibody; P represents H, OH or an activated O; and L represents a specific linker. The disclosure also relates to cryptophycin payloads, as well as to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The disclosure also relates to the process for preparing these conjugates.
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Page/Page column 210; 211
(2018/12/02)
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- HDAC INHIBITORS-BASED ANTIBODY DRUG CONJUGATES (ADCs) AND USE IN THERAPY
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The present invention relates to novel Histone Deacetylase Inhibitors (HDACi)- based antibody drug conjugates particularly with antibodies directed to ErbB1, ErbB2 and ErbB3 receptors, pharmaceutical compositions comprising said antibodies as well as to their use in the treatment of cancer or tumor and other diseases where a modulation of one or more histone deacetylase isoforms can be effective for therapeutic interventions.
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Page/Page column 64-66
(2018/10/25)
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- Cysteine-transformed antibody-toxin conjugate and its preparation method
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The invention discloses a cysteine-transformed antibody-toxin conjugate and its preparation method. The cysteine-transformed antibody-toxin conjugate with excellent uniformity is formed by inserting aheavy chain and a light chain of a target antibody to the cysteine (C) at the fixed point, and performing fixed-point coupling on a free sulfydryl (-SH) of the cysteine inserted at the fixed point and a connector coupled with micromolecular high-activity cell toxin. The insert site of the cysteine disclosed in the invention is the 205th site and/or the 206th site (Kabat number) of the antibody light chain, and/or the 439th site of the heavy chain (Kabat number).
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Paragraph 0067; 0068; 0069
(2018/03/25)
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- AMANITIN ANTIBODY CONJUGATES
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The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6'-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a BCMA-binding moiety comprising (i) the variable domains of humanized antibody J22.9-ISY, and (ii) a heavy chain constant region comprising a D265C mutation; and (c) a protease-cleavable linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate, particularly for use in the treatment of multiple myeloma.
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Paragraph 00103; 00124; 00125
(2018/07/29)
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- Cysteine engineered antibody - toxin conjugate (TDC) fixed-point coupling site screening (by machine translation)
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The invention discloses a cysteine engineered antibody - toxin conjugate, characterized in that the antibody is the antibody fixed-point inserted cysteine, cysteine insertion site comprises a site selected from the following group of one or more of: light chain constant region of the light chain kappa / λ 110 position, section 111 position, section 142 bit, IgG antibody heavy chain constant region of the heavy chain of the 254 bit, of the 255 bit, of the 258 position, section 259 bit, section 354 bit, section 355 bit, part 357 bit, paragraph 378 bit, article 379 bit, section 386 bit, article 387 bit or 410 bit. (by machine translation)
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Paragraph 0010; 0011; 0012
(2018/11/22)
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- Cysteine transformation-based antibody-toxin conjugate
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Heavy chain 235-site serine (S) and light chain 205-site valine (V) of a target antibody are transformed into cysteine (C), and after transformation, free sulfhydryl (-SH) of the cysteine is coupled to a mc-vc-PAB-OH connexon coupled with small molecular high-activity cytotoxin (Payload) in a fixed-point way to form a cysteine transformation-based antibody-toxin conjugate with good uniformity; thetoxin-antibody ratio (DAR) of the cysteine transformation-based antibody-toxin conjugate is 3.2-4.0, and the antibody-toxin conjugate adopts a general formula of 1C7-HC-S235C-LC-V205C-mc-vc-PAB-payload. The invention further discloses a preparation method and a purification method of a TDC medicine and application to treatment of EGFRwt (wild-type epidermal growth factor receptor) overexpressionrelated tumors.
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Paragraph 0014-0016
(2018/11/22)
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- ALDEHYDE CAPTURE LIGATION TECHNOLOGY FOR SYNTHESIS OF AMIDE BONDS
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The present invention relates to ligation agents and their use in making an amide ligation product. Methods of making the ligation agents are also disclosed.
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Paragraph 0284; 0285
(2017/09/13)
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- AMANITIN CONJUGATES
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The invention relates to a conjugate comprising (a) an amatoxin comprising (i) an amino acid 4 with a 6'-deoxy position; and (ii) an amino acid 8 with an S-deoxy position; (b) a target-binding moiety; and (c) optionally a linker linking said amatoxin and said target-binding moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.
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Paragraph 00128-00129
(2017/09/15)
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- POLYCONJUGATES FOR DELIVERY OF RNAI TRIGGERS TO TUMOR CELLS IN VIVO
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The present invention is directed compositions for delivery of RNA interference (RNAi) triggers to integrin positive tumor cells in vivo. The compositions comprise RGD ligand- targeted amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or conjugate) are further covalently linked to an RNAi trigger.
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Page/Page column 36
(2015/02/25)
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- HYDROPHILIC LINKERS AND THEIR USES FOR CONJUGATION OF DRUGS TO CELL BINDING MOLECULES
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Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.
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- IMMUNOMODULATORY CONJUGATES
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The present invention provides an immunomodulatory compound comprising a carbohydrate polymer comprising mannose, wherein the carbohydrate polymer is conjugated to at least one immune modulator. The present invention also provides for the use of this compound in immunomodulatory compositions for vaccination and gene therapy methods, together with processes for its preparation.
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Page/Page column 80
(2013/05/23)
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- A facile synthesis and crystallographic analysis of N-protected β-amino alcohols and short peptaibols
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A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.
- Jadhav, Sandip V.,Bandyopadhyay, Anupam,Benke, Sushil N.,Mali, Sachitanand M.,Gopi, Hosahudya N.
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supporting information; experimental part
p. 4182 - 4187
(2011/06/28)
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- The use of a cysteinyl prolyl ester (CPE) autoactivating unit in peptide ligation reactions
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A peptide containing a cysteinyl prolyl ester (CPE) moiety at the C-terminus (CPE peptide) is spontaneously transformed into a diketopiperazine thioester via an intramolecular N-S acyl shift reaction, followed by diketopiperazine formation. The CPE peptide can be ligated with a Cys-peptide in a one-pot procedure. The peptide diketopiperazine thioester can also be transformed into a peptide thioester by intermolecular thiol-thioester exchange with external thiol compounds such as sodium mercaptoethanesulfonate. Since CPE peptides can be prepared by standard Fmoc solid-phase synthesis, it is a versatile alternative to the peptide thioester, providing a flexible ligation strategy that promises to be useful in polypeptide synthesis.
- Kawakami, Toru,Aimoto, Saburo
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body text
p. 3871 - 3877
(2009/09/30)
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- Branched peptide linkers
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Conjugates containing a targeting ligand, such as an antibody, a therapeutically active drug and a branched peptide linker. The branched peptide linker contains two or more amino acid moieties that provide an enzyme cleavage site. The number of drugs capable of being bonded to the branched linkers varies by a factor of two for each generation of branching.
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- O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis
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The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.
- Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
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p. 1661 - 1664
(2007/10/03)
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- In the search for new anticancer drugs. 28. Synthesis and evaluation of highly active aminoxyl labeled amino acid derivatives containing the [N'-(2- chloroethyl)-N'-nitrosoamino]carbonyl group
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The aminoxyl (nitroxyl) labeled (2-chloroethyl)nitrosocarbamoyl (CNC) derivatives of amino acids, i.e., N-[[N'-(2-chloroethyl)-N'- nitrosoamino]carbonyl]-A-(1-oxy-2,2,6,6-tetramethylpiperidin-4-yl)amides, A = glycyl (10a), A = L-alanyl (10b), A = L-valyl (10c), A = L-phenylalanyl (10d), were synthesized and evaluated in vitro for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 10a-d possessed activities ranging from 242 to 456% increase in life span (%ILS). All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 30 days. Compounds 10a-d were then tested in vivo against the murine lymphoid leukemia L1210. Compounds 10a-d exhibited, on day 60, a %ILS of 496, 663, 663, and 581, respectively. All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 60 days. The lipophilicities of compounds 10a-d were determined using the UV method. The %ILS parameters obtained against the P388 and L1210 tumor lines were correlated with the corresponding lipophilicities, and a trend was generally observed toward an increase in cytotoxicity with a concomitant decrease in hydrophobicity.
- Sosnovsky,Baysal,Erciyas
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p. 999 - 1005
(2007/10/02)
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