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Journal articles on the topic 'Peptide Prodrugs'

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Published: 10 December 2022

Last updated: 29 January 2023

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1

Zhang, Richard, and Haishan Lin. "Abstract 5204: Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5204. http://dx.doi.org/10.1158/1538-7445.am2022-5204.

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Abstract CD47 is a well-studied target for cancer immunotherapy. Blocking of CD47 binding to its receptor, SIRPα, on macrophages leads to inhibition of macrophage activation and phagocytosis. Several monoclonal anti-CD47 antibodies are currently in various stages of clinical development. However, since CD47 is also expressed on normal cells such as red blood cells and platelets, anti-CD47 antibodies also caused on-target side effects during clinical evaluations, such as anemia and red blood cell hemagglutination. To minimize the on-target side effects of anti-CD47 antibodies, we have generated anti-CD47 prodrugs. By screening a phage peptide library, we identified peptides that can specifically block the anti-CD47 antibody binding activity. These peptides were fused to the humanized anti-CD47 antibody via a linker containing protease substrate sequences to derive the anti-CD47 antibody prodrug. We demonstrated that these anti-CD47 antibody prodrugs had significantly diminished CD47 binding activity and were unable to block CD47:SIRPα interaction. Upon cleavage of the anti-CD47 antibody prodrug with proteases, the antibody regained full activities in both binding to CD47 and blocking CD47:SIRPα interaction. Importantly, we showed that the anti-CD47 antibody prodrug had minimal hemagglutination and RBC binding activities. Since different tumors may have different types of protease activities, anti-CD47 prodrugs with different types of protease substrates have been generated to demonstrate that the anti-CD47 prodrug can be used for treating various tumor types. These data suggest that novel anti-CD47 antibody prodrugs are promising candidates for the next generation anti-CD47 therapeutics with improved safety profile. Citation Format: Richard Zhang, Haishan Lin. Optimization of novel anti-human CD47 antibody prodrugs as cancer therapeutics with low on-target toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5204.

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2

THOMAS, W. A. "Peptide derivatives as prodrugs." Biochemical Society Transactions 14, no. 2 (April 1, 1986): 383–87. http://dx.doi.org/10.1042/bst0140383.

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3

McKenna, Charles E., Boris A. Kashemirov, Ulrika Eriksson, Gordon L. Amidon, Phillip E. Kish, Stefanie Mitchell, Jae-Seung Kim, and John M. Hilfinger. "Cidofovir peptide conjugates as prodrugs." Journal of Organometallic Chemistry 690, no. 10 (May 2005): 2673–78. http://dx.doi.org/10.1016/j.jorganchem.2005.03.004.

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4

Janssen, Samuel, Carsten M. Jakobsen, D. Marc Rosen, Rebecca M. Ricklis, Ulrich Reineke, Soeren B. Christensen, Hans Lilja, and Samuel R. Denmeade. "Screening a combinatorial peptide library to develop a human glandular kallikrein 2–activated prodrug as targeted therapy for prostate cancer." Molecular Cancer Therapeutics 3, no. 11 (November 1, 2004): 1439–50. http://dx.doi.org/10.1158/1535-7163.1439.3.11.

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Abstract Objective: Prostate cancer cells secrete the unique protease human glandular kallikrein 2 (hK2) that represents a target for proteolytic activation of cytotoxic prodrugs. The objective of this study was to identify hK2-selective peptide substrates that could be coupled to a cytotoxic analogue of thapsigargin, a potent inhibitor of the sarcoplasmic/endoplasmic reticulum calcium ATPase pump that induces cell proliferation–independent apoptosis through dysregulation of intracellular calcium levels. Methods: To identify peptide sequence requirements for hK2, a combination of membrane-bound peptides (SPOT analysis) and combinatorial chemistry using fluorescence-quenched peptide substrates was used. Peptide substrates were then coupled to 8-O-(12[l-leucinoylamino]dodecanoyl)-8-O-debutanoylthapsigargin (L12ADT), a potent analogue of thapsigargin, to produce a prodrug that was then characterized for hK2 hydrolysis, plasma stability, and in vitro cytotoxicity. Results: Both techniques indicated that a peptide with two arginines NH2-terminal of the scissile bond produced the highest rates of hydrolysis. A lead peptide substrate with the sequence Gly-Lys-Ala-Phe-Arg-Arg (GKAFRR) was hydrolyzed by hK2 with a Km of 26.5 μmol/L, kcat of 1.09 s−1, and a kcat/Km ratio of 41,132 s−1 mol/L−1. The GKAFRR-L12ADT prodrug was rapidly hydrolyzed by hK2 and was stable in plasma, whereas the GKAFRR-L peptide substrate was unstable in human plasma. The hK2-activated thapsigargin prodrug was not activated by cathepsin B, cathepsin D, and urokinase but was an excellent substrate for plasmin. The GKAFRR-L12ADT was selectively cytotoxic in vitro to cancer cells in the presence of enzymatically active hK2. Conclusion: The hK2-activated thapsigargin prodrug represents potential novel targeted therapy for prostate cancer.

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5

Forde, Éanna, Hilary Humphreys, Catherine M. Greene, Deirdre Fitzgerald-Hughes, and Marc Devocelle. "Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis." Antimicrobial Agents and Chemotherapy 58, no. 2 (November 25, 2013): 978–85. http://dx.doi.org/10.1128/aac.01167-13.

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ABSTRACTHost defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities ofPseudomonas aeruginosato parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates ofP. aeruginosa. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme atin vivoconcentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.

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6

Forde, Eanna, and Marc Devocelle. "Pro-Moieties of Antimicrobial Peptide Prodrugs." Molecules 20, no. 1 (January 13, 2015): 1210–27. http://dx.doi.org/10.3390/molecules20011210.

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7

Forde, Éanna, André Schütte, Emer Reeves, Catherine Greene, Hilary Humphreys, Marcus Mall, Deirdre Fitzgerald-Hughes, and Marc Devocelle. "DifferentialIn VitroandIn VivoToxicities of Antimicrobial Peptide Prodrugs for Potential Use in Cystic Fibrosis." Antimicrobial Agents and Chemotherapy 60, no. 5 (February 22, 2016): 2813–21. http://dx.doi.org/10.1128/aac.00157-16.

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ABSTRACTThere has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial agents for the treatment of many conditions, including cystic fibrosis (CF). The challenging conditions of the CF patient lung require robust AMPs that are active in an environment of high proteolytic activity but that also have low cytotoxicity and immunogenicity. Previously, we developed prodrugs of AMPs that limited the cytotoxic effects of AMP treatment by rendering the antimicrobial activity dependent on the host enzyme neutrophil elastase (NE). However, cytotoxicity remained an issue. Here, we describe the further optimization of the AMP prodrug (pro-AMP) model for CF to produce pro-WMR, a peptide with greatly reduced cytotoxicity (50% inhibitory concentration against CFBE41o- cells, >300 μM) compared to that of the previous group of pro-AMPs. The bactericidal activity of pro-WMR was increased in NE-rich bronchoalveolar lavage (BAL) fluid from CF patients (range, 8.4% ± 6.9% alone to 91.5% ± 5.8% with BAL fluid;P= 0.0004), an activity differential greater than that of previous pro-AMPs. In a murine model of lung delivery, the pro-AMP modification reduced host toxicity, with pro-WMR being less toxic than the active peptide. Previously, host toxicity issues have hampered the clinical application of AMPs. However, the development of application-specific AMPs with modifications that minimize toxicity similar to those described here can significantly advance their potential use in patients. The combination of this prodrug strategy with a highly active AMP has the potential to produce new therapeutics for the challenging conditions of the CF patient lung.

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8

Wei, Yaoming, and Dehua Pei. "Activation of antibacterial prodrugs by peptide deformylase." Bioorganic & Medicinal Chemistry Letters 10, no. 10 (May 2000): 1073–76. http://dx.doi.org/10.1016/s0960-894x(00)00167-0.

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9

Lee, Jiyoun, Wei Huang, James M. Broering, Annelise E. Barron, and Jiwon Seo. "Prostate tumor specific peptide–peptoid hybrid prodrugs." Bioorganic & Medicinal Chemistry Letters 25, no. 14 (July 2015): 2849–52. http://dx.doi.org/10.1016/j.bmcl.2015.04.092.

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10

Freeman, Hanna, Selvi Srinivasan, Debobrato Das, Patrick S. Stayton, and Anthony J. Convertine. "Fully synthetic macromolecular prodrug chemotherapeutics with EGFR targeting and controlled camptothecin release kinetics." Polymer Chemistry 9, no. 42 (2018): 5224–33. http://dx.doi.org/10.1039/c8py01047a.

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11

Wong, Daniel Yuan Qiang, Jun Han Lim, and Wee Han Ang. "Induction of targeted necrosis with HER2-targeted platinum(iv) anticancer prodrugs." Chemical Science 6, no. 5 (2015): 3051–56. http://dx.doi.org/10.1039/c5sc00015g.

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Platinum(iv) prodrug complexes based on the cisplatin/oxaliplatin pharmacophore, containing anti-HER2/neu targeting peptides, were designed to deliver their cytotoxic platinum(ii) payload selectively to highly HER2-expressing cells. Through induction of necrotic cell death, these platinum(iv)–peptide conjugates can circumvent apoptosis-resistance pathways in targeted HER2-positive cells.

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12

Tewari, K. M., E. Yaghini, O. Reelfs, R. Dondi, C. Pourzand, A. J. MacRobert, and I. M. Eggleston. "Peptide-targeted prodrugs for aminolaevulinic acid photodynamic therapy." Photodiagnosis and Photodynamic Therapy 17 (March 2017): A60. http://dx.doi.org/10.1016/j.pdpdt.2017.01.135.

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13

Yang, Seong-Bin, Nipa Banik, Bomin Han, Dong-Nyeong Lee, and Jooho Park. "Peptide-Based Bioconjugates and Therapeutics for Targeted Anticancer Therapy." Pharmaceutics 14, no. 7 (June 29, 2022): 1378. http://dx.doi.org/10.3390/pharmaceutics14071378.

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With rapidly growing knowledge in bioinformatics related to peptides and proteins, amino acid-based drug-design strategies have recently gained importance in pharmaceutics. In the past, peptide-based biomedicines were not widely used due to the associated severe physiological problems, such as low selectivity and rapid degradation in biological systems. However, various interesting peptide-based therapeutics combined with drug-delivery systems have recently emerged. Many of these candidates have been developed for anticancer therapy that requires precisely targeted effects and low toxicity. These research trends have become more diverse and complex owing to nanomedicine and antibody–drug conjugates (ADC), showing excellent therapeutic efficacy. Various newly developed peptide–drug conjugates (PDC), peptide-based nanoparticles, and prodrugs could represent a promising therapeutic strategy for patients. In this review, we provide valuable insights into rational drug design and development for future pharmaceutics.

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14

Langley, Emma, Chen Li, Jessica Zaid, Tani-Ann Lee, Deepak Yadav, Brian Grot, Jay Singh, and Johnovan Kim. "713 Novel protease activatable linker with tumor targeting motifs enhances the retention of cytokine prodrug and active cytokine at disease site and demonstrates improved efficacy in preclinical model." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A742. http://dx.doi.org/10.1136/jitc-2021-sitc2021.713.

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BackgroundAn emerging class of new protease-activatable prodrugs designed to enhance on-target activity and reduce off-target toxicity are being actively developed. Cytokines are complex immune mediators which display potent anti-tumor activity in preclinical models and have delivered clinical responses in several advanced tumor types. However, clinical development of cytokine therapies has been hampered by high systemic toxicity, a narrow therapeutic index and short circulatory half-life. To address these shortcomings, we have developed next-generation cytokine therapies, On Demand Cytokines or ODCs.MethodsODCs are protease-activatable cytokine prodrugs in which the cytokine is linked to an inhibitory moiety via a short proprietary peptide motif. These recombinant proteins are designed to exploit the protease activity present within the tumor microenvironment (TME) and enable the local release of active cytokine to trigger an anti-tumor immune response. ODCs contain tumor stroma targeting elements to further enhance their retention and activation within the malignant tissue. We have developed an array of stromaphilic ODCs, including a panel of IL-2 prodrugs containing single or dual tumor stroma binding motifs and report their preclinical in vitro and in vivo characterization.ResultsAll IL-2 prodrugs were successfully manufactured and activated in vitro by Matrix Metalloprotease cleavage which triggered the release of functional cytokine. Binding of prodrugs to tumor stroma components was confirmed in vitro. The ODC-IL2 panel was tested in vivo as single agent in the subcutaneous syngeneic B16F10 melanoma model. The uncleaved drugs were retained in the tumor at 5 to 20-fold higher levels than a control cytokine prodrug lacking any tumor targeting elements. Furthermore, intratumoral levels of IL-2 and IFNg were increased 8 to 80-fold and 10 to 40-fold respectively compared to cytokine levels measured in the control non-targeted ODC treated arm. Finally, stromaphilic ODCs displayed substantially enhanced levels in circulation over non-targeted ODC. Superior anti-tumor efficacy was observed for all stroma targeting pro-cytokines with near complete tumor growth inhibition achieved with the dual targeting site construct.ConclusionsWe have demonstrated that the On Demand Cytokine platform can generate protease-activatable cytokine prodrugs with enhanced tumor retention and on-target activity, to ultimately deliver safer and more effective immunotherapies.

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15

WANG, HUI-PO, HSIAO-HWA LU, JIA-SHUAI LEE, CHIH-YUAN CHENG, JIN-RAN MAH, CHING-YI KU, WENLIE HSU, CHEN-FANG YEN, CHUN-JUNG LIN, and HARNG S. KUO. "Intestinal Absorption Studies on Peptide Mimetic α-Methyldopa Prodrugs." Journal of Pharmacy and Pharmacology 48, no. 3 (March 1996): 270–76. http://dx.doi.org/10.1111/j.2042-7158.1996.tb05915.x.

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16

Henrique Goulart Trossini, Gustavo, Chung Man Chin, Carla Maria de Souza Menezes, and Elizabeth Igne Ferreira. "Molecular Modeling Suggests Cruzain Specificity for Peptide Primaquine Prodrugs." Letters in Drug Design & Discovery 7, no. 7 (August 1, 2010): 528–33. http://dx.doi.org/10.2174/157018010791526287.

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17

Palandoken, Hasan, Kolbot By, Manu Hegde, William R. Harley, Fredric A. Gorin, and Michael H. Nantz. "Amiloride Peptide Conjugates: Prodrugs for Sodium-Proton Exchange Inhibition." Journal of Pharmacology and Experimental Therapeutics 312, no. 3 (October 27, 2004): 961–67. http://dx.doi.org/10.1124/jpet.104.076984.

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18

Bourré, Ludovic, Francesca Giuntini, Ian M. Eggleston, Michael Wilson, and Alexander J. MacRobert. "5-Aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy." Molecular Cancer Therapeutics 7, no. 6 (June 2008): 1720–29. http://dx.doi.org/10.1158/1535-7163.mct-08-0092.

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19

Nollmann, Friederike Inga, Tina Goldbach, Nicole Berthold, and Ralf Hoffmann. "Kontrollierte systemische Freisetzung therapeutischer Peptide aus PEGylierten Prodrugs durch Serumproteasen." Angewandte Chemie 125, no. 29 (June 13, 2013): 7747–50. http://dx.doi.org/10.1002/ange.201301533.

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20

Agarwal, Sheetal, S. H. S. Boddu, Ritesh Jain, Swapan Samanta, Dhananjay Pal, and Ashim K. Mitra. "Peptide prodrugs: Improved oral absorption of lopinavir, a HIV protease inhibitor." International Journal of Pharmaceutics 359, no. 1-2 (July 2008): 7–14. http://dx.doi.org/10.1016/j.ijpharm.2008.03.031.

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21

BACKWELL, F. R. C., D. T. ELMORE, and C. H. WILLIAMS. "The use of neuropeptidases to release drug from peptide-based prodrugs." Biochemical Society Transactions 16, no. 2 (April 1, 1988): 214–15. http://dx.doi.org/10.1042/bst0160214a.

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22

Weiss, William J., Susan M. Mikels, Peter J. Petersen, Nilda V. Jacobus, Panayota Bitha, Yang-I. Lin, and Raymond T. Testa. "In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems." Antimicrobial Agents and Chemotherapy 43, no. 3 (March 1, 1999): 460–64. http://dx.doi.org/10.1128/aac.43.3.460.

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ABSTRACT A series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while the d forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused by S. aureus, E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii,Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

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23

Cooper, Itzik, Michal Schnaider-Beeri, Mati Fridkin, and Yoram Shechter. "Albumin–Methotrexate Prodrug Analogues That Undergo Intracellular Reactivation Following Entrance into Cancerous Glioma Cells." Pharmaceutics 14, no. 1 (December 28, 2021): 71. http://dx.doi.org/10.3390/pharmaceutics14010071.

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A family of monomodified bovine serum albumin (BSA) linked to methotrexate (MTX) through a variety of spacers was prepared. All analogues were found to be prodrugs having low MTX-inhibitory potencies toward dihydrofolate reductase in a cell-free system. The optimal conjugates regenerated their antiproliferative efficacies following entrance into cancerous glioma cell lines and were significantly superior to MTX in an insensitive glioma cell line. A BSA–MTX conjugate linked through a simple ethylene chain spacer, containing a single peptide bond located 8.7 Å distal to the protein back bone, and apart from the covalently linked MTX by about 12 Å, was most effective. The inclusion of an additional disulfide bond in the spacer neither enhanced nor reduced the killing potency of this analogue. Disrupting the native structure of the carrier protein in the conjugates significantly reduced their antiproliferative activity. In conclusion, we have engineered BSA–MTX prodrug analogues which undergo intracellular reactivation and facilitate antiproliferative activities following their entrance into glioma cells.

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Cho, Hanhee, Man Kyu Shim, Suah Yang, Sukyung Song, Yujeong Moon, Jinseong Kim, Youngro Byun, Cheol-Hee Ahn, and Kwangmeyung Kim. "Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy." Pharmaceutics 14, no. 1 (December 29, 2021): 83. http://dx.doi.org/10.3390/pharmaceutics14010083.

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Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine.

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Li, Xuejiao, Yahong Liu, and Hongqi Tian. "Current Developments in Pt(IV) Prodrugs Conjugated with Bioactive Ligands." Bioinorganic Chemistry and Applications 2018 (October 1, 2018): 1–18. http://dx.doi.org/10.1155/2018/8276139.

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To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase hydrophobicity, conjugation with short peptide chains or nanoparticles to improve drug delivery, or addition of bioactive ligands to the axial positions of Pt(IV) complexes to exert dual-function effects. This review summarizes the recent progress in the development of Pt(IV) prodrugs conjugated with bioactive-targeting ligands, including histone deacetylase inhibitors, p53 agonists, alkylating agents, and nonsteroidal anti-inflammatory agents. Although Pt(IV) complexes that conjugated with bioactive ligands show satisfactory anticancer effects, none has been approved for clinical use. Therefore, we hope that this review will contribute to further study and development of Pt(IV) complexes conjugated with bioactive and other ligands.

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26

Wang, Binghe, Wei Wang, Huijuan Zhang, Daxian Shan, and Terrill D. Smith. "Coumarin-based prodrugs 2. Synthesis and bioreversibility studies of an esterase-sensitive cyclic prodrug of dadle, an opioid peptide." Bioorganic & Medicinal Chemistry Letters 6, no. 23 (December 1996): 2823–26. http://dx.doi.org/10.1016/s0960-894x(96)00526-4.

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27

Janoria, Kumar G., Sai H. S. Boddu, Subramanian Natesan, and Ashim K. Mitra. "Vitreal Pharmacokinetics of Peptide-Transporter-Targeted Prodrugs of Ganciclovir in Conscious Animals." Journal of Ocular Pharmacology and Therapeutics 26, no. 3 (June 2010): 265–71. http://dx.doi.org/10.1089/jop.2009.0123.

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28

Schmid, Björn, André Warnecke, Iduna Fichtner, Manfred Jung, and Felix Kratz. "Development of Albumin-Binding Camptothecin Prodrugs Using a Peptide Positional Scanning Library." Bioconjugate Chemistry 18, no. 6 (November 2007): 1786–99. http://dx.doi.org/10.1021/bc0700842.

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29

Nasrolahi Shirazi, Amir, Rakesh Tiwari, Bhupender S. Chhikara, Dindyal Mandal, and Keykavous Parang. "Design and Biological Evaluation of Cell-Penetrating Peptide–Doxorubicin Conjugates as Prodrugs." Molecular Pharmaceutics 10, no. 2 (January 15, 2013): 488–99. http://dx.doi.org/10.1021/mp3004034.

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30

Eriksson, Ulrika, Larryn W. Peterson, Boris A. Kashemirov, John M. Hilfinger, John C. Drach, Katherine Z. Borysko, Julie M. Breitenbach, et al. "Serine Peptide Phosphoester Prodrugs of Cyclic Cidofovir: Synthesis, Transport, and Antiviral Activity." Molecular Pharmaceutics 5, no. 4 (May 16, 2008): 598–609. http://dx.doi.org/10.1021/mp8000099.

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31

De, Arnab, and Richard D. DiMarchi. "Synthesis and characterization of ester-based prodrugs of glucagon-like peptide 1." Biopolymers 94, no. 4 (June 30, 2010): 448–56. http://dx.doi.org/10.1002/bip.21418.

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32

Matošević, Ana, and Anita Bosak. "Carbamate group as structural motif in drugs: a review of carbamate derivatives used as therapeutic agents." Archives of Industrial Hygiene and Toxicology 71, no. 4 (December 1, 2020): 285–99. http://dx.doi.org/10.2478/aiht-2020-71-3466.

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Abstract Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer’s disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.

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Wang, Caihong, Chu Chu, Xiang Ji, Guoliang Luo, Chunling Xu, Houhong He, Jianbiao Yao, Jian Wu, Jiangning Hu, and Yuanxiang Jin. "Biology of Peptide Transporter 2 in Mammals: New Insights into Its Function, Structure and Regulation." Cells 11, no. 18 (September 14, 2022): 2874. http://dx.doi.org/10.3390/cells11182874.

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Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also of significant medical and pharmacological significance in the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, β-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. In this review, we provide a comprehensive overview of the structure, substrate preferences and localization of PepT2 in mammals. As PepT2 is expressed in various organs, its function in the liver, kidney, brain, heart, lung and mammary gland has also been addressed. Finally, the regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed.

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Ouyang, Liang, Wencai Huang, Gu He, and Li Guo. "Bone Targeting Prodrugs Based on Peptide Dendrimers, Synthesis and Hydroxyapatite Binding In Vitro." Letters in Organic Chemistry 6, no. 4 (June 1, 2009): 272–77. http://dx.doi.org/10.2174/157017809788489981.

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35

Chin, Chung, Diego Chiba, Marcella Machado, Ednir Vizioli, and Jean Santos. "Peptide Prodrugs for the Treatment of CNS Disorders: A Perspective for New Drugs." Current Medicinal Chemistry 21, no. 23 (February 17, 2014): 2599–609. http://dx.doi.org/10.2174/0929867321666140217125526.

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Poreba, Marcin. "Recent advances in the development of legumain-selective chemical probes and peptide prodrugs." Biological Chemistry 400, no. 12 (December 18, 2019): 1529–50. http://dx.doi.org/10.1515/hsz-2019-0135.

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Abstract Legumain, which is also known as vacuolar processing enzyme (VPE) or asparaginyl endopeptidase (AEP), is a cysteine protease that was first discovered and characterized in the leguminous seeds of the moth bean in the early 1990s. Later, this enzyme was also detected in higher organisms, including eukaryotes. This pH-dependent protease displays the highest activity in acidic endolysosomal compartments; however, legumain also displays nuclear, cytosolic and extracellular activity when stabilized by other proteins or intramolecular complexes. Based on the results from over 25 years of research, this protease is involved in multiple cellular events, including protein degradation and antigen presentation. Moreover, when dysregulated, this protease contributes to the progression of several diseases, with cancer being the well-studied example. Research on legumain biology was undoubtedly facilitated by the use of small molecule chemical tools. Therefore, in this review, I present the historical perspectives and most current strategies for the development of small molecule substrates, inhibitors and activity-based probes for legumain. These tools are of paramount importance in elucidating the roles of legumain in multiple biological processes. Finally, as this enzyme appears to be a promising molecular target for anticancer therapies, the development of legumain-activated prodrugs is also described.

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Giuntini, Francesca, Ludovic Bourré, Alexander J. MacRobert, Michael Wilson, and Ian M. Eggleston. "Improved Peptide Prodrugs of 5-ALA for PDT: Rationalization of Cellular Accumulation and Protoporphyrin IX Production by Direct Determination of Cellular Prodrug Uptake and Prodrug Metabolization." Journal of Medicinal Chemistry 52, no. 13 (July 9, 2009): 4026–37. http://dx.doi.org/10.1021/jm900224r.

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Roseeuw, Eveline, Veerle Coessens, Anne-Marie Balazuc, Micheline Lagranderie, Pierre Chavarot, Augusto Pessina, Maria Grazia Neri, Etienne Schacht, Gilles Marchal, and Dominique Domurado. "Synthesis, Degradation, and Antimicrobial Properties of Targeted Macromolecular Prodrugs of Norfloxacin." Antimicrobial Agents and Chemotherapy 47, no. 11 (November 2003): 3435–41. http://dx.doi.org/10.1128/aac.47.11.3435-3441.2003.

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ABSTRACT Long-term antibiotic treatment is required to cure tuberculosis. Targeted antibiotics should improve the efficacy of treatment by concentrating the drugs close to the bacteria. The aim of the present study was to synthesize targeted conjugates. For this purpose, we used mannose as a homing device to direct norfloxacin into macrophages. Dextran was used as the polymer bearing both mannose and norfloxacin. Using different peptide spacer arms to link norfloxacin to dextran, we demonstrated that norfloxacin acts as an antibiotic only when it is released in its native form. Also, targeting by using mannose as a homing device is required to achieve antimycobacterial activity in vivo. Thus, norfloxacin, which is inactive against mycobacteria in its native form in vivo, can be transformed into an active drug by targeting.

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Hu, Zilun, Xiangjun Jiang, Charles F. Albright, Nilsa Graciani, Eddy Yue, Mingzhu Zhang, Shu-Yun Zhang, et al. "Discovery of matrix metalloproteases selective and activated peptide–doxorubicin prodrugs as anti-tumor agents." Bioorganic & Medicinal Chemistry Letters 20, no. 3 (February 2010): 853–56. http://dx.doi.org/10.1016/j.bmcl.2009.12.084.

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Polykandritou, Athina, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, and Robert A. Falconer. "Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1074. http://dx.doi.org/10.1158/1538-7445.am2022-1074.

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Abstract ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs. 1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3 Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1074.

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Oliyai, Reza, and Valentino J. Stella. "Structural Factors affecting the kinetics of O,N-acyl transfer in potential O-peptide prodrugs." Bioorganic & Medicinal Chemistry Letters 5, no. 22 (November 1995): 2735–40. http://dx.doi.org/10.1016/0960-894x(95)00454-2.

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Shaik, Imam H., Hitesh K. Agarwal, Keykavous Parang, and Reza Mehvar. "Hepatic immunosuppressive effects of systemically administered novel dextran–methylprednisolone prodrugs with peptide linkers in rats." Journal of Pharmaceutical Sciences 101, no. 10 (October 2012): 4003–12. http://dx.doi.org/10.1002/jps.23274.

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Friis, Gitte Juel, Annette Bak, Bjarne Due Larsen, and Sven Frøkjær. "Prodrugs of peptides obtained by derivatization of the C-terminal peptide bond in order to effect protection against degradation by carboxypeptidases." International Journal of Pharmaceutics 136, no. 1-2 (June 1996): 61–69. http://dx.doi.org/10.1016/0378-5173(95)04481-7.

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Kumar, Ritesh, Amrish Chandra, and Pawan Kumar Gautam. "Modified Approaches for Colon Specific Drug Delivery System: A Review." Indian Journal of Pharmaceutical and Biological Research 1, no. 03 (September 30, 2013): 67–79. http://dx.doi.org/10.30750/ijpbr.1.3.12.

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The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review mainly describes the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules. Oral administration of different dosage forms is the most commonly used method due to flexibility in design of dosage form and high patient acceptance, but the gastrointestinal tract presents several formidable barriers to drug delivery. In oral colon-specific drug delivery system, colon has a large amount of lymphoma tissue (facilitates direct absorption in to the blood), negligible brush boarder membrane activity, and much less pancreatic enzymatic activity as compared with the small intestine. Colon-specific drug delivery has gained increased importance not just for the delivery of the drugs for treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides. Different approaches are designed based on prodrug formulation, pH-sensitivity, time-dependency (lag time), microbial degradation and osmotic pressure etc to formulate the different dosage forms like tablets, capsules, multiparticulates, microspheres, liposomes for colon targeting. The delivery of drugs to the colon has a number of therapeutic implications in the field of drug delivery. In the recent times, the colon specific delivery systems are also gaining importance not only for local drug delivery of drugs but also for the systemic delivery of protein and peptide drugs. This review updated the research on different approaches formulation and evaluation of colon-specific drug delivery.

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Prokai-Tatrai, Katalin, Vien Nguyen, Alevtina D. Zharikova, April C. Braddy, Stanley M. Stevens, and Laszlo Prokai. "Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2." Bioorganic & Medicinal Chemistry Letters 13, no. 6 (March 2003): 1011–14. http://dx.doi.org/10.1016/s0960-894x(03)00081-7.

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Saaby, L., C. U. Nielsen, B. Steffansen, S. B. Larsen, and B. Brodin. "Current status of rational design of prodrugs targeting the intestinal di/tri-peptide transporter hPEPT1 (SLC15A1)." Journal of Drug Delivery Science and Technology 23, no. 4 (2013): 307–14. http://dx.doi.org/10.1016/s1773-2247(13)50047-5.

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Aloysius, Herve, and Longqin Hu. "Synthesis and evaluation of new peptide-linked doxorubicin conjugates as prodrugs activated by prostate-specific antigen." Medicinal Chemistry Research 29, no. 7 (June 4, 2020): 1280–99. http://dx.doi.org/10.1007/s00044-020-02573-w.

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Wu, Xinghua, and Longqin Hu. "Design and synthesis of peptide conjugates of phosphoramide mustard as prodrugs activated by prostate-specific antigen." Bioorganic & Medicinal Chemistry 24, no. 12 (June 2016): 2697–706. http://dx.doi.org/10.1016/j.bmc.2016.04.035.

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Verhulst, Emile, Delphine Garnier, Ingrid De Meester, and Brigitte Bauvois. "Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?" Cancers 14, no. 3 (January 26, 2022): 624. http://dx.doi.org/10.3390/cancers14030624.

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Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.

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Kwant, Kathryn, Sony Rocha, Katrina Stephenson, Maria Dayao, Subramanian Thothathri, Rose Banzon, Wade Aaron, et al. "867 TriTAC-XR is an extended-release T cell engager platform designed to minimize cytokine release syndrome by reducing Cmax in systemic circulation." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A908. http://dx.doi.org/10.1136/jitc-2021-sitc2021.867.

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BackgroundCD3-targeted T cell engagers are potent anti-tumor therapies, but their development often requires management of cytokine release syndrome (CRS). Subcutaneous dosing is a promising strategy to reduce CRS, but its application is limited by its increased immunogenicity risks. Subcutaneous dosing is hypothesized to mitigate CRS by reducing the maximum drug concentration (Cmax) and preserve efficacy by maintaining the same minimum drug concentration (Cmin) as intravenous dosing. A T cell engager designed to be dosed intravenously but engineered to mimic the PK properties of subcutaneous dosing could alleviate CRS without increasing immunogenicity.MethodsTriTAC-XR molecules are engineered T cell engager prodrugs that become slowly activated in systemic circulation. This extended-release mechanism results in a slow build-up of circulating active drug, similar to subcutaneous dosing, and extends drug exposure to enable longer dosing intervals. The prodrug was engineered by adding a peptide mask and protease-cleavable linker to the N-terminus of a TriTAC, a constitutively active and half-life extended T cell engager. The mask binds to the anti-CD3ε domain and prevents T cell binding. Upon cleavage by systemic proteases, active T cell engager is released. Binding was assessed using ELISA on recombinant CD3ε protein and using flow cytometry on primary T cells. T cell engager function was assessed using T cell-dependent cellular cytotoxicity (TDCC) assays with resting human T cells. Safety and efficacy were modeled in non-human primates.ResultsTriTAC-XR had markedly reduced binding to recombinant CD3ε protein and to primary T cells as well as reduced potency in functional TDCC assays compared to its unmasked active drug. In cynomolgus monkeys, TriTAC-XR had significantly attenuated cytokine production while maintaining comparable pharmacodynamic effects as a non-masked active drug. The ratio of Cmax to Cmin for the active TriTAC-XR was significantly smaller than a non-masked control.ConclusionsTriTAC-XR is activated in a time released manner by systemic proteases to minimize differences between the Cmax and Cmin of systemic active drug. This mechanism is different from other protease-activated T cell engager prodrugs that are only activated by tumor-associated proteases. Compared to canonical T cell engagers, TriTAC-XR is expected to improve safety by reducing CRS and to provide convenience by extending dosing intervals.

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