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Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.

ABSTRACT: Although celebrating its golden jubilee, rapamycin's importance keeps increasing by the day. Starting as a promising antifungal agent, then as a potent immunosuppressant, strong anticancer drug, and now rapamycin is attracting serious attention as a rejuvenative agent and a possible contributor in treating this era pandemic, COVID-19. Due to its diverse biological activities and promising medical applications, we aimed in this review to put rapamycin under the spot and highlight its discovery, famous microbial producers, reported biological activities, chemical structure, famous analogues, and biosynthesis. Moreover, discuss some rapamycin production approaches including solid-state fermentation, and stressing out producing strain. On the other hand, describe its action mechanism and trials to use it in treatment of COVID-19. Additionally, we highlighted some of the side effects accompanying its use, and describe some approaches reported to minimize these undesired effects. Finally, we report the current status of rapamycin and its analogues in global market, and discuss future prospects of this potent drug.

SUBMITTER: Mohamed MA

PROVIDER: S-EPMC9188914 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.

Mohamed Mohamed A MA Elkhateeb Waill A WA Daba Ghoson M GM

Bioresources and bioprocessing 20220613 1

Although celebrating its golden jubilee, rapamycin's importance keeps increasing by the day. Starting as a promising antifungal agent, then as a potent immunosuppressant, strong anticancer drug, and now rapamycin is attracting serious attention as a rejuvenative agent and a possible contributor in treating this era pandemic, COVID-19. Due to its diverse biological activities and promising medical applications, we aimed in this review to put rapamycin under the spot and highlight its discovery, f ...[more]

PMID: 35730039

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Project description:Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, including malignant melanomas, drug-selected resistant cell lines, specific ABC transporter-overexpressing cell lines, and the National Cancer Institute 60 cell line panel. DJ95 treatment inhibited cancer cell migration, caused morphologic changes to the microtubule network foundation, and severely disrupted mitotic spindle formation of mitotic cells. The high-resolution crystal structure of DJ95 in complex with tubulin protein and the detailed molecular interactions confirmed its direct binding to the colchicine site. In vitro pharmacological screening of DJ95 using SafetyScreen44 (Eurofins Cerep-Panlabs) revealed no significant off-target interactions, and pharmacokinetic analysis showed that DJ95 was maintained at therapeutically relevant plasma concentrations for up to 24 hours in mice. In an A375 xenograft model in nude mice, DJ95 inhibited tumor growth and disrupted tumor vasculature in xenograft tumors. These results demonstrate that DJ95 is potent against a variety of cell lines, demonstrated greater potency to ABC transporter-overexpressing cell lines than existing tubulin inhibitors, directly targets the colchicine binding domain, exhibits significant antitumor efficacy, and demonstrates vascular-disrupting properties. Collectively, these data suggest that DJ95 has great potential as a cancer therapeutic, particularly for multidrug resistance phenotypes, and warrants further development. SIGNIFICANCE STATEMENT: Paclitaxel is a widely used tubulin inhibitor for cancer therapy, but its clinical efficacy is often limited by the development of multidrug resistance. In this study, we reported the preclinical characterization of a new tubulin inhibitor DJ95, and demonstrated its abilities to overcome paclitaxel resistance, disrupt tumor vasculature, and exhibit significant antitumor efficacy.

Dataset Information

Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.

Publications

Rapamycin golden jubilee and still the miraculous drug: a potent immunosuppressant, antitumor, rejuvenative agent, and potential contributor in COVID-19 treatment.

Similar Datasets

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