-
Molecules (Basel, Switzerland) Jan 2015Antimicrobial peptides (AMPs) are a promising class of antimicrobial agents that have been garnering increasing attention as resistance renders many conventional... (Review)
Review
Antimicrobial peptides (AMPs) are a promising class of antimicrobial agents that have been garnering increasing attention as resistance renders many conventional antibiotics ineffective. Extensive research has resulted in a large library of highly-active AMPs. However, several issues serve as an impediment to their clinical development, not least the issue of host toxicity. An approach that may allow otherwise cytotoxic AMPs to be used is to deliver them as a prodrug, targeting antimicrobial activity and limiting toxic effects on the host. The varied library of AMPs is complemented by a selection of different possible pro-moieties, each with their own characteristics. This review deals with the different pro-moieties that have been used with AMPs and discusses the merits of each.
Topics: Anti-Infective Agents; Peptides; Prodrugs
PubMed: 25591121
DOI: 10.3390/molecules20011210 -
Advanced Healthcare Materials May 2022Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of...
Engineered immune cells are an exciting therapeutic modality, which survey and attack tumors. Backpacking strategies exploit cell targeting capabilities for delivery of drugs to combat tumors and their immune-suppressive environments. Here, a new platform for arming cell therapeutics through dual receptor and polymeric prodrug engineering is developed. Macrophage and T cell therapeutics are engineered to express a bioorthogonal single chain variable fragment receptor. The receptor binds a fluorescein ligand that directs cell loading with ligand-tagged polymeric prodrugs, termed "drugamers." The fluorescein ligand facilitates stable binding of drugamer to engineered macrophages over 10 days with 80% surface retention. Drugamers also incorporate prodrug monomers of the phosphoinositide-3-kinase inhibitor, PI-103. The extended release of PI-103 from the drugamer sustains antiproliferative activity against a glioblastoma cell line compared to the parent drug. The versatility and modularity of this cell arming system is demonstrated by loading T cells with a second fluorescein-drugamer. This drugamer incorporates a small molecule estrogen analog, CMP8, which stabilizes a degron-tagged transgene to provide temporal regulation of protein activity in engineered T cells. These results demonstrate that this bioorthogonal receptor and drugamer system can be used to arm multiple immune cell classes with both antitumor and transgene-activating small molecule prodrugs.
Topics: Fluoresceins; Humans; Ligands; Neoplasms; Polymers; Prodrugs
PubMed: 34889072
DOI: 10.1002/adhm.202101944 -
Antiviral Chemistry & Chemotherapy 2018Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has... (Review)
Review
Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.
Topics: Amides; Antiviral Agents; Humans; Microbial Sensitivity Tests; Molecular Structure; Phosphoric Acids; Prodrugs; Viruses
PubMed: 29792071
DOI: 10.1177/2040206618775243 -
Biomaterials Dec 2023In the design of delivery strategies for anticancer therapeutics, the controlled release of intact cargo at the destined tumor and metastasis locations is of particular... (Review)
Review
In the design of delivery strategies for anticancer therapeutics, the controlled release of intact cargo at the destined tumor and metastasis locations is of particular importance. To this end, stimuli-responsive chemical linkers have been extensively investigated owing to their ability to respond to tumor-specific physiological stimuli, such as lowered pH, altered redox conditions, increased radical oxygen species and pathological enzymatic activities. To prevent premature action and off-target effects, anticancer therapeutics are chemically modified to be transiently inactivated, a strategy known as prodrug development. Prodrugs are reactivated upon stimuli-dependent release at the sites of interest. As most drugs and therapeutic proteins have the optimal activity when released from carriers in their native and original forms, traceless release mechanisms are increasingly investigated. In this review, we summarize the chemical toolkit for developing innovative traceless prodrug strategies for stimuli-responsive drug delivery and discuss the applications of these chemical modifications in anticancer treatment including cancer immunotherapy.
Topics: Humans; Prodrugs; Drug Delivery Systems; Neoplasms; Drug Carriers; Nanoparticles
PubMed: 37925794
DOI: 10.1016/j.biomaterials.2023.122353 -
Medicinal Chemistry (Shariqah (United... Jul 2012Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often... (Review)
Review
Poor bioavailability of topically instilled drug is the major concern in the field of ocular drug delivery. Efflux transporters, static and dynamic ocular barriers often possess rate limiting factors for ocular drug therapy. Different formulation strategies like suspension, ointment, gels, nanoparticles, implants, dendrimers and liposomes have been employed in order to improve drug permeation and retention by evading rate limiting factors at the site of absorption. Chemical modification such as prodrug targeting various nutrient transporters (amino acids, peptide and vitamin) has evolved a great deal of interest to improve ocular drug delivery. In this review, we have discussed various prodrug strategies which have been widely applied for enhancing therapeutic efficacy of ophthalmic drugs. The purpose of this review is to provide an update on the utilization of prodrug concept in ocular drug delivery. In addition, this review will highlight ongoing academic and industrial research and development in terms of ocular prodrug design and delivery.
Topics: Administration, Ophthalmic; Drug Delivery Systems; Humans; Prodrugs
PubMed: 22530907
DOI: 10.2174/157340612801216283 -
International Journal of Molecular... May 2019The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature,...
The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood-brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A (PLA)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.
Topics: Animals; Antigens, Human Platelet; Drug Design; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Phospholipids; Prodrugs; Substrate Specificity
PubMed: 31060339
DOI: 10.3390/ijms20092210 -
ACS Chemical Biology May 2021In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an...
In light of the continued threat of antimicrobial-resistant bacteria, new strategies to expand the repertoire of antimicrobial compounds are necessary. Prodrugs are an underexploited strategy in this effort. Here, we report on the enhanced antimicrobial activity of a prodrug toward bacteria having an enzyme capable of its activation. A screen led us to the sulfurol ester of the antibiotic -3-(4-chlorobenzoyl)acrylic acid. An endogenous esterase makes sensitive to this prodrug. Candidate esterases were identified, and their heterologous production made sensitive to the ester prodrug. Taken together, these data suggest a new approach to the development of antimicrobial compounds that takes advantage of endogenous enzymatic activities to target specific bacteria.
Topics: Acrylates; Anti-Infective Agents; Bacillus subtilis; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Escherichia coli; Esterases; Esters; Mycobacterium smegmatis; Prodrugs; Structure-Activity Relationship
PubMed: 33877811
DOI: 10.1021/acschembio.0c00894 -
Chemical Society Reviews Jun 2024Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with... (Review)
Review
Polymer prodrugs are based on the covalent linkage of therapeutic molecules to a polymer structure which avoids the problems and limitations commonly encountered with traditional drug-loaded nanocarriers in which drugs are just physically entrapped (, burst release, poor drug loadings). In the past few years, reversible-deactivation radical polymerization (RDRP) techniques have been extensively used to design tailor-made polymer prodrug nanocarriers. This synthesis strategy has received a lot of attention due to the possibility of fine tuning their structural parameters (, polymer nature and macromolecular characteristics, linker nature, physico-chemical properties, functionalization, ), to achieve optimized drug delivery and therapeutic efficacy. In particular, adjusting the nature of the drug-polymer linker has enabled the easy synthesis of stimuli-responsive polymer prodrugs for efficient spatiotemporal drug release. In this context, this review article will give an overview of the different stimuli-sensitive polymer prodrug structures designed by RDRP techniques, with a strong focus on the synthesis strategies, the macromolecular architectures and in particular the drug-polymer linker, which governs the drug release kinetics and eventually the therapeutic effect. Their biological evaluations will also be discussed.
Topics: Prodrugs; Polymerization; Drug Carriers; Humans; Polymers; Nanoparticles; Drug Liberation; Free Radicals
PubMed: 38775004
DOI: 10.1039/d2cs01060g -
Theranostics 2022Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly...
Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
Topics: Doxorubicin; Glucuronidase; Humans; Neoplasms; Prodrugs
PubMed: 35832083
DOI: 10.7150/thno.69168 -
Molecules (Basel, Switzerland) Nov 2020Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack... (Review)
Review
Prodrugs, which remain inert until they are activated under appropriate conditions at the target site, have emerged as an attractive alternative to drugs that lack selectivity and show off-target effects. Prodrugs have traditionally been activated by enzymes, pH or other trigger factors associated with the disease. In recent years, bioorthogonal chemistry has allowed the creation of prodrugs that can be chemically activated with spatio-temporal precision. In particular, tetrazine-responsive bioorthogonal reactions can rapidly activate prodrugs with excellent biocompatibility. This review summarized the recent development of tetrazine bioorthogonal cleavage reaction and great promise for prodrug systems.
Topics: Activation, Metabolic; Animals; Cycloaddition Reaction; Drug Delivery Systems; Heterocyclic Compounds; Humans; Prodrugs
PubMed: 33266075
DOI: 10.3390/molecules25235640