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Expert Opinion on Therapeutic Targets 2023Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity.... (Review)
Review
INTRODUCTION
Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy.
AREAS COVERED
Triphenylphosphonium cation (TPP)-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP-based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies.
EXPERT OPINION
TPP-based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP-based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP-based OXPHOS-inhibiting drugs in cancer prevention and treatment.
Topics: Humans; Mice; Animals; Mitochondria; Oxidative Phosphorylation; Neoplasms; Drug Delivery Systems; Antineoplastic Agents
PubMed: 37736880
DOI: 10.1080/14728222.2023.2261631 -
Pathogens (Basel, Switzerland) Sep 2021Babesiosis is an emerging tick-borne disease caused by apicomplexan parasites of the genus . With its increasing incidence worldwide and the risk of human-to-human... (Review)
Review
Babesiosis is an emerging tick-borne disease caused by apicomplexan parasites of the genus . With its increasing incidence worldwide and the risk of human-to-human transmission through blood transfusion, babesiosis is becoming a rising public health concern. The current arsenal for the treatment of human babesiosis is limited and consists of combinations of atovaquone and azithromycin or clindamycin and quinine. These combination therapies were not designed based on biological criteria unique to parasites, but were rather repurposed based on their well-established efficacy against other apicomplexan parasites. However, these compounds are associated with mild or severe adverse events and a rapid emergence of drug resistance, thus highlighting the need for new therapeutic strategies that are specifically tailored to parasites. Herein, we review ongoing babesiosis therapeutic and management strategies and their limitations, and further review current efforts to develop new, effective, and safer therapies for the treatment of this disease.
PubMed: 34578153
DOI: 10.3390/pathogens10091120 -
The Medical Letter on Drugs and... Oct 2019
Review
Topics: Animals; Antimalarials; Diarrhea; Humans; Insect Bites and Stings; Malaria; Travel; Travel-Related Illness
PubMed: 31599872
DOI: No ID Found -
Molecules (Basel, Switzerland) May 2021Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete.... (Review)
Review
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Topics: Acyclovir; Atenolol; Atovaquone; Catalysis; Chemistry, Pharmaceutical; Decitabine; Dopamine; Enzymes; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Molecular Conformation; Nucleosides; Phenylephrine; Prodrugs; Protons; Quantum Theory; Software; Technology, Pharmaceutical; Temperature; Tranexamic Acid
PubMed: 34071328
DOI: 10.3390/molecules26113248 -
Reproduction (Cambridge, England) Jun 2023Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study...
IN BRIEF
Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis.
ABSTRACT
Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.
Topics: Female; Humans; Curcumin; Atovaquone; Antimalarials; Oxidative Phosphorylation; Endometriosis; NAD; Antineoplastic Agents; Cell Proliferation
PubMed: 37068140
DOI: 10.1530/REP-22-0265 -
BMC Cancer Nov 2023Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are...
BACKGROUND
Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer.
METHODS
To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification.
RESULTS
This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone.
CONCLUSION
In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
Topics: Animals; Humans; NF-kappa B; Atovaquone; Cell Line, Tumor; Signal Transduction; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 37932661
DOI: 10.1186/s12885-023-11585-9 -
Briefings in Functional Genomics Sep 2019Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all... (Review)
Review
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
Topics: Aminoquinolines; Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Resistance, Multiple; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Plasmodium vivax; Quinine
PubMed: 31119263
DOI: 10.1093/bfgp/elz008 -
Journal of Clinical Medicine Jan 2022Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug...
Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.
PubMed: 35160232
DOI: 10.3390/jcm11030781 -
Biomedicine & Pharmacotherapy =... Jun 2023The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved...
The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
Topics: Humans; Antiviral Agents; SARS-CoV-2; COVID-19; Dihydroorotate Dehydrogenase; Drug Repositioning; Dronedarone; Pandemics; Atovaquone; Mebendazole; Purines; Molecular Docking Simulation; Protease Inhibitors; Molecular Dynamics Simulation
PubMed: 37068330
DOI: 10.1016/j.biopha.2023.114614 -
European Journal of Medicinal Chemistry Dec 2023The opportunistic apicomplexan parasite Toxoplasma gondii is the etiologic agent for toxoplasmosis, which can infect a widespread range of hosts, particularly humans and... (Review)
Review
The opportunistic apicomplexan parasite Toxoplasma gondii is the etiologic agent for toxoplasmosis, which can infect a widespread range of hosts, particularly humans and warm-blooded animals. The present chemotherapy to treat or prevent toxoplasmosis is deficient and is based on diverse drugs such as atovaquone, trimethoprim, spiramycine, which are effective in acute toxoplasmosis. Therefore, a safe chemotherapy is required for toxoplasmosis considering that its responsible agent, T. gondii, provokes severe illness and death in pregnant women and immunodeficient patients. A certain disadvantage of the available treatments is the lack of effectiveness against the tissue cyst of the parasite. A safe chemotherapy to combat toxoplasmosis should be based on the metabolic differences between the parasite and the mammalian host. This article covers different relevant molecular targets to combat this disease including the isoprenoid pathway (farnesyl diphosphate synthase, squalene synthase), dihydrofolate reductase, calcium-dependent protein kinases, histone deacetylase, mitochondrial electron transport chain, etc.
Topics: Animals; Humans; Female; Pregnancy; Toxoplasma; Toxoplasmosis; Atovaquone; Trimethoprim; Mammals
PubMed: 37871407
DOI: 10.1016/j.ejmech.2023.115885