scholarly journals Enzymatic Non-Covalent Synthesis of a Versatile Platform for Bioorthogonal Prodrugs Activation to Combat Drug Resistance

2020 ◽  
Author(s):  
Qingxin Yao ◽  
Shuo Gao ◽  
Chengling Wu ◽  
Ting Lin ◽  
Yuan Gao
Keyword(s):  
Therapeutic Index ◽  
Bioactive Molecules ◽  
Therapeutic Window ◽  
Dose Ratio ◽  
Prodrug Activation ◽  
Safety And Efficacy ◽  
Anticancer Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Multidrug resistance (MDR) often leads to the failure of the anticancer treatment. Besides the blockage of those MDR pathways, the development of more potent drugs are of urgent needs but largely postponed due to imbalance between safety and efficacy. The prodrug strategy, especially with bioorthogonal activation has shown immerse potential to <a>balance safety and efficacy</a>, while recent studies focus on few drug entities such as doxorubicin and MMAE, leaving the vast collection of toxins undetermined. Here we <a>have enumerate</a>d typical molecular entities ranging from FDA approved drugs (doxorubicin, paclitaxel) to a heated ADC warhead (MMAF-OMe) and a <a>trichothecene</a> toxin (Mytoxin A) to demonstrate that the <i>trans</i>-cyclooctene (TCO) caging may serve as a general prodrug design to increase the therapeutic index for bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution is regulated by the cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. These cell-specific prodrugs activation could not only reduce the toxicology of drugs but also enhance the synergistic therapeutic effect within a broad range of dose ratio. More importantly, these prodrugs activation share the same activator bearing assemblies, which allows the flexible shift of drug identities to successfully combat MDR cancer <i>in vivo</i>. In general, this versatile bioorthogonal prodrug activation platform is readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled prodrug activation should facilitate the drug discovery and development.<br>

scholarly journals Enzymatic Non-Covalent Synthesis of a Versatile Platform for Bioorthogonal Prodrugs Activation to Combat Drug Resistance

2020 ◽  
Author(s):  
Qingxin Yao ◽  
Shuo Gao ◽  
Chengling Wu ◽  
Ting Lin ◽  
Yuan Gao
Keyword(s):  
Therapeutic Index ◽  
Bioactive Molecules ◽  
Therapeutic Window ◽  
Dose Ratio ◽  
Prodrug Activation ◽  
Safety And Efficacy ◽  
Anticancer Treatment ◽  
Approved Drugs ◽  
Fda Approved Drugs

Multidrug resistance (MDR) often leads to the failure of the anticancer treatment. Besides the blockage of those MDR pathways, the development of more potent drugs are of urgent needs but largely postponed due to imbalance between safety and efficacy. The prodrug strategy, especially with bioorthogonal activation has shown immerse potential to <a>balance safety and efficacy</a>, while recent studies focus on few drug entities such as doxorubicin and MMAE, leaving the vast collection of toxins undetermined. Here we <a>have enumerate</a>d typical molecular entities ranging from FDA approved drugs (doxorubicin, paclitaxel) to a heated ADC warhead (MMAF-OMe) and a <a>trichothecene</a> toxin (Mytoxin A) to demonstrate that the <i>trans</i>-cyclooctene (TCO) caging may serve as a general prodrug design to increase the therapeutic index for bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution is regulated by the cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. These cell-specific prodrugs activation could not only reduce the toxicology of drugs but also enhance the synergistic therapeutic effect within a broad range of dose ratio. More importantly, these prodrugs activation share the same activator bearing assemblies, which allows the flexible shift of drug identities to successfully combat MDR cancer <i>in vivo</i>. In general, this versatile bioorthogonal prodrug activation platform is readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled prodrug activation should facilitate the drug discovery and development.<br>

scholarly journals Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain

2021 ◽  
Vol 118 (10) ◽  
pp. e2016265118
Author(s):  
Mahmoud S. Ahmed ◽  
Ping Wang ◽  
Ngoc Uyen Nhi Nguyen ◽  
Yuji Nakada ◽  
Ivan Menendez-Montes ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Therapeutic Option ◽  
Atp Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Pharmacokinetic drug–drug interactions: an insight into recent US FDA-approved drugs for prostate cancer

Bioanalysis ◽  
2020 ◽  
Vol 12 (22) ◽  
pp. 1647-1664
Author(s):  
Siva Nageswara Rao Gajula ◽  
Gangireddy Navitha Reddy ◽  
Dannarm Srinivas Reddy ◽  
Rajesh Sonti
Keyword(s):  
Drug Interactions ◽  
Therapeutic Index ◽  
Aged Patients ◽  
Metabolizing Enzymes ◽  
Considerable Concentration ◽  
Concentration Changes ◽  
Us Fda ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Pharmacokinetic Drug

Pharmacokinetic drug–drug interaction is a significant safety and efficiency concern as it results in considerable concentration changes. Drug–drug interactions are a substantial concern in anticancer drugs that possess a narrow therapeutic index. These interactions remain as the principal regulatory obstacle that can lead to termination in the preclinical stage, restrictions in the prescription, dosage adjustments or withdrawal of the drugs from the market. Drug metabolizing enzymes or transporters mediate the majority of clinically relevant drug interactions. Cancer diagnosed aged patients use multiple medications and are more prone to significant drug–drug interactions. This review provides detailed information on clinically relevant drug–drug interactions resulting from drug metabolism by enzymes and transporters with a particular emphasis on recent FDA approved antiprostate cancer drugs.

Molecular modification of a recombinant anti-CD3ε-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1157-1165 ◽  
Author(s):  
Daniel A. Vallera ◽  
David W. Kuroki ◽  
Angela Panoskaltsis-Mortari ◽  
Donald J. Buchsbaum ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Cysteine Residue ◽  
Genetically Engineered ◽  
Therapeutic Window ◽  
Single Chain ◽  
Molecular Modification ◽  
Organ Toxicity

Abstract Immunotoxin (IT) therapy shows potential for selectively eliminating GVHD-causing T cells in vivo, but the field has been hampered by toxicity. Previously, we showed that a genetically engineered IT consisting of a single-chain protein, including the anti-CD3sFv spliced to a portion of diphtheria-toxin (DT390) has anti-GVHD effects, but pronounced organ toxicity common to this class of agent. A recombinant DT390 anti-CD3sFv protein previously shown to have anti-GVHD activity was modified to reduce its filtration into kidney by genetically inserting a cysteine residue downstream of the sFv moiety at the c-terminus of the protein. This modification produced an intermolecular disulfide bridge, resulting in a bivalent, rather than a monovalent IT, termed SS2, that selectively inhibited T-cell proliferation in vitro. Although monomer and SS2 were similar in in vitro activity, SS2 had a superior therapeutic index in vivo with at least 8-fold more being tolerated with reduced kidney toxicity. Most importantly, in a lethal model of GVHD, 40 μg SS2 given for 1 day, protected 100% of the mice from lethal GVHD for 3 months, whereas the maximum tolerated dose (MTD) of monomer protected only 33%. To our knowledge, this is the first time disulfide bonded ITs have been created in this way and this simple molecular modification may address several problems in the IT field because it (1) markedly increased efficacy curing mice of GVHD after a single daily treatment, (2) markedly decreased organ toxicity, (3) increased the tolerated dosage, and (4) created a therapeutic window where none existed before.

Molecular modification of a recombinant anti-CD3ε-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1157-1165 ◽  
Author(s):  
Daniel A. Vallera ◽  
David W. Kuroki ◽  
Angela Panoskaltsis-Mortari ◽  
Donald J. Buchsbaum ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Cysteine Residue ◽  
Genetically Engineered ◽  
Therapeutic Window ◽  
Single Chain ◽  
Molecular Modification ◽  
Organ Toxicity

Immunotoxin (IT) therapy shows potential for selectively eliminating GVHD-causing T cells in vivo, but the field has been hampered by toxicity. Previously, we showed that a genetically engineered IT consisting of a single-chain protein, including the anti-CD3sFv spliced to a portion of diphtheria-toxin (DT390) has anti-GVHD effects, but pronounced organ toxicity common to this class of agent. A recombinant DT390 anti-CD3sFv protein previously shown to have anti-GVHD activity was modified to reduce its filtration into kidney by genetically inserting a cysteine residue downstream of the sFv moiety at the c-terminus of the protein. This modification produced an intermolecular disulfide bridge, resulting in a bivalent, rather than a monovalent IT, termed SS2, that selectively inhibited T-cell proliferation in vitro. Although monomer and SS2 were similar in in vitro activity, SS2 had a superior therapeutic index in vivo with at least 8-fold more being tolerated with reduced kidney toxicity. Most importantly, in a lethal model of GVHD, 40 μg SS2 given for 1 day, protected 100% of the mice from lethal GVHD for 3 months, whereas the maximum tolerated dose (MTD) of monomer protected only 33%. To our knowledge, this is the first time disulfide bonded ITs have been created in this way and this simple molecular modification may address several problems in the IT field because it (1) markedly increased efficacy curing mice of GVHD after a single daily treatment, (2) markedly decreased organ toxicity, (3) increased the tolerated dosage, and (4) created a therapeutic window where none existed before.

scholarly journals A platform utilizing Drosophila ovulation for nonhormonal contraceptive screening

2021 ◽  
Vol 118 (28) ◽  
pp. e2026403118
Author(s):  
Kewa Jiang ◽  
Jiyang Zhang ◽  
Yuping Huang ◽  
Yingzheng Wang ◽  
Shuo Xiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Unmet Need ◽  
Dependent Manner ◽  
Female Reproduction ◽  
Contraceptive Agents ◽  
Follicle Rupture ◽  
Approved Drugs ◽  
Fda Approved Drugs

A significant unmet need for new contraceptive options for both women and men remains due to side-effect profiles, medical concerns, and the inconvenience of many currently available contraceptive products. Unfortunately, the development of novel nonsteroidal female contraceptive medicine has been stalled in the last couple of decades due to the lack of effective screening platforms. Drosophila utilizes conserved signaling pathways for follicle rupture, a final step in ovulation that is essential for female reproduction. Therefore, we explored the potential to use Drosophila as a model to screen compounds that could inhibit follicle rupture and be nonsteroidal contraceptive candidates. Using our ex vivo follicle rupture assay, we screened 1,172 Food and Drug Administration (FDA)–approved drugs and identified six drugs that could inhibit Drosophila follicle rupture in a dose-dependent manner. In addition, we characterized the molecular actions of these drugs in the inhibition of adrenergic signaling and follicle rupture. Furthermore, we validated that three of the four drugs consistently inhibited mouse follicle rupture in vitro and that two of them did not affect progesterone production. Finally, we showed that chlorpromazine, one of the candidate drugs, can significantly inhibit mouse follicle rupture in vivo. Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these FDA-approved drugs as novel nonsteroidal contraceptive agents.

scholarly journals Sulfisoxazole does not inhibit the secretion of small extracellular vesicles

2020 ◽  
Author(s):  
Pamali Fonseka ◽  
Sai V Chitti ◽  
Rahul Sanwlani ◽  
Suresh Mathivanan
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Breast Cancer Cells ◽  
Drug Repurposing ◽  
Tumor Burden ◽  
Immunocompetent Mouse ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractRecently, the study by Im et al. focused on blocking the release of extracellular vesicles (EVs) by cancer cells, as a strategy to block metastasis, by deploying a drug repurposing screen. Upon screening the library of FDA approved drugs in breast cancer cells in vitro, the authors reported the ability of the antibiotic Sulfisoxazole (SFX) in inhibiting EV biogenesis and secretion. SFX was also effective in reducing breast primary tumor burden and blocking metastasis in immunocompromised and immunocompetent mouse models. As we seek a compound to block EV biogenesis and secretion in our current in vivo studies, we intended to use SFX and hence performed in vitro characterization as the first step. However, treatment of two cancer cells with SFX did not reduce the amount of EVs as reported by the authors.

Potential Papain-like Protease Inhibitors against COVID-19: A Comprehensive In Silico Based Review

2021 ◽  
Vol 25 ◽  
Author(s):  
Neetu Agrawal ◽  
Shilpi Pathak ◽  
Ahsas Goyal
Keyword(s):  
In Silico ◽  
Chemical Compounds ◽  
Potential Candidate ◽  
In Vivo Experiments ◽  
Drug Databases ◽  
In Silico Studies ◽  
Approved Drugs ◽  
Fda Approved Drugs

: The entire world has been in a battle against the COVID-19 pandemic since its first appearance in December 2019. Thus researchers are desperately working to find an effective and safe therapeutic agent for its treatment. The multifunctional coronavirus enzyme papain-like protease (PLpro) is a potential target for drug discovery to combat the ongoing pandemic responsible for cleavage of the polypeptide, deISGylation, and suppression of host immune response. The present review collates the in silico studies performed on various FDA-approved drugs, chemical compounds, and phytochemicals from various drug databases and represents the compounds possessing the potential to inhibit PLpro. Thus this review can provide quick access to a potential candidate to medicinal chemists to perform in vitro and in vivo experiments who are thriving to find the effective agents for the treatment of COVID-19.

scholarly journals New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

2016 ◽  
Vol 60 (6) ◽  
pp. 3717-3729 ◽  
Author(s):  
Jourdan A. Andersson ◽  
Eric C. Fitts ◽  
Michelle L. Kirtley ◽  
Duraisamy Ponnusamy ◽  
Alex G. Peniche ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Bacterial Pathogens ◽  
Bactericidal Effect ◽  
Resistant Bacteria ◽  
Content Type ◽  
Broad Applicability ◽  
Approved Drugs ◽  
Fda Approved Drugs

Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulentYersinia pestisCO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventingY. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy inin vitroscreens, were chosen for further evaluation in a murine model of pneumonic plague to delineate ifin vitroefficacy could be translatedin vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect onY. pestisand having no modulating effect on crucialY. pestisvirulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified fromin vitroscreens, the therapeutic potential of TFP, the most efficacious drugin vivo, was evaluated in murine models ofSalmonella entericaserovar Typhimurium andClostridium difficileinfections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

scholarly journals Broad anti-coronaviral activity of FDA approved drugs against SARS-CoV-2 in vitro and SARS-CoV in vivo

2020 ◽  
Author(s):  
Stuart Weston ◽  
Christopher M. Coleman ◽  
Rob Haupt ◽  
James Logue ◽  
Krystal Matthews ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Ic50 Values ◽  
Human Use ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractSARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with roughly 2.7 million recorded COVID-19 cases and greater than 189,000 recorded deaths by April 23rd, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A quick way to test compounds with potential antiviral activity is through drug repurposing. Numerous drugs are already approved for human use and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV. We found that 17 of these inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. We directly follow up with seven of these to demonstrate all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we have evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found both drugs protect mice from clinical disease.

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