Carboxypeptidase-mediated release of methotrexate from methotrexate .alpha.-peptides

Kuefner, U.; Lohrmann, Ute; Montejano, Yolanda D.; Vitols, Κ.S.; Huennekens, F.M.

doi:10.1021/bi00431a047

Cited by 55 publications

(34 citation statements)

References 21 publications

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“…Many synthetic schemes have been reported to selectively obtain MTX-α-amino acid derivatives in high yield (17,18). Using the method reported by Coughlin et al (19), α-amino acid-conjugated prodrugs were synthesized (Fig.…”

Section: Synthesis Of Prodrugsmentioning

confidence: 99%

Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

et al. 2011

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Section: Synthesis Of Prodrugsmentioning

confidence: 99%

Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

et al. 2011

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“…This can be avoided by coupling the Glu-amino acid dipeptide to 4-amino-4-deoxy-10-methylpteroic acid. Hydrolysis of the MTX oc-peptides by various carboxypeptidases, and particularly MTXAla by carboxypeptidase-A (CP-Α), has been examined in detail (2). These reactions, although slow relative to the rates with standard substrates for the enzymes (e.g.. hippurylphenylalanine for CP-Α), are still sufficient to generate toxic quantities of the drug (2).…”

Section: Division Of Biochemistry Department Of Molecular and Experimentioning

confidence: 99%

Activation of Methotrexate Prodrugs by Enzyme/Monoclonal Antibody Conjugates

et al. 1991

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One of the major goals in cancer chemotherapy is the development of procedures for the selective delivery of drugs to tumor cells. This strategy, when perfected, will allow drugs to be used at the high concentrations necessary for virtually complete (i. e., > 99%) eradication of the tumor cells without concomitant destruction of normal cells. Monoclonal antibodies targeted to tumor antigens offer considerable promise for effecting the desired selectivity. To date, however, only limited success has been achieved in clinical trials with monoclonals as vehicles for carrying drugs. Two limitations are evident in the use of drug-monoclonal conjugates: (a) Relatively few drug molecules can be linked to each monoclonal without impairing binding activity; and (b) A mechanism is needed to release covalently-bound drug from the antibody. In an effort to overcome these problems, attention has focused recently on the attachment of enzymes rather than drugs to monoclonals, thereby taking advantage of the catalytic power of the enzyme to generate large amounts of the active drugs from inert prodrugs at the tumor site [reviewed by Senter (1)].Methotrexate (MTX), employed extensively in cancer chemotherapy, is well-suited to the prodrug/enzymemonoclonal conjugate strategy. α-Peptides of the drug (i.e., derivatives in which the a-COOH has been linked to an amino acid) are relatively non-toxic, but these derivatives can be hydrolyzed by carboxypep-" Recipient of an EORTC Fellowship. Present address: Institute

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“…In 1989, Kuefner et al . synthesized a panel of methotrexate‐based prodrugs containing aspartic acid (Asp), Arg, or Ala amino acids. These prodrugs were designed to be activated by cathepsin B, which under some conditions may display carboxypeptidase‐like activity.…”

Section: Peptide Prodrugsmentioning

confidence: 99%

Protease‐activated prodrugs: strategies, challenges, and future directions

Poręba

2020

The FEBS Journal

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Proteases play critical roles in virtually all biological processes, including proliferation, cell death and survival, protein turnover, and migration. However, when dysregulated, these enzymes contribute to the progression of multiple diseases, with cancer, neurodegenerative disorders, inflammation, and blood disorders being the most prominent examples. For a long time, disease-associated proteases have been used for the activation of various prodrugs due to their well-characterized catalytic activity and ability to selectively cleave only those substrates that strictly correspond with their active site architecture. To date, versatile peptide sequences that are cleaved by proteases in a site-specific manner have been utilized as bioactive linkers for the targeted delivery of multiple types of cargo, including fluorescent dyes, photosensitizers, cytotoxic drugs, antibiotics, and pro-antibodies. This platform is highly adaptive, as multiple protease-labile conjugates have already been developed, some of which are currently in clinical use for cancer treatment. In this review, recent advancements in the development of novel protease-cleavable linkers for selective drug delivery are described. Moreover, the current limitations regarding the selectivity of linkers are Abbreviations AAC, antibody-antibiotic conjugate; Ab, antibody; ACC, 7-amino-4-carbamoylmethylcoumarin; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; ADC, antibody-drug conjugate; aPSs, activatable photosensitizers; BHQ-3, black hole quencher 3; Boc, tert-butyloxycarbonyl group; BT20, a type of mammary gland carcinoma; Cas9, CRISPR-associated protein 9;

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Carboxypeptidase-mediated release of methotrexate from methotrexate .alpha.-peptides

Cited by 55 publications

References 21 publications

Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

Novel Integrin-Targeted Binding-Triggered Drug Delivery System for Methotrexate

Activation of Methotrexate Prodrugs by Enzyme/Monoclonal Antibody Conjugates

Protease‐activated prodrugs: strategies, challenges, and future directions

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