-
Journal of Virology Jun 2019Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In...
Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA-approved drugs. In this study, we addressed the antiviral role of atovaquone, an FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides, indicating that atovaquone functions through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner, providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children. The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease, yet this has not been explored in detail. In this study, we show that the common antiparasitic drug atovaquone inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.
Topics: Animals; Antiviral Agents; Arboviruses; Atovaquone; Cell Line; Chikungunya Fever; Chikungunya virus; Chlorocebus aethiops; Cytoplasm; Female; HEK293 Cells; Humans; Placenta; Pregnancy; Pyrimidine Nucleotides; Pyrimidines; Vero Cells; Viral Nonstructural Proteins; Virion; Virus Internalization; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 30894466
DOI: 10.1128/JVI.00389-19 -
Expert Review of Anti-infective Therapy Dec 2005Increases in international travel and escalating drug resistance have resulted in a growing number of travelers at risk of contracting malaria. Drug resistance and... (Review)
Review
Increases in international travel and escalating drug resistance have resulted in a growing number of travelers at risk of contracting malaria. Drug resistance and intolerance to standard agents such as chloroquine, sulfadoxine/pyrimethamine and mefloquine has highlighted the need for new antimalarials. The recently licensed fixed combination of atovaquone and proguanil hydrochloride (Malarone) is a promising new agent to prevent and treat Plasmodium falciparum malaria. Randomized controlled trials have shown that atovaquone/proguanil is well tolerated and efficacious for the prevention and treatment of drug-resistant P. falciparum malaria. Atovaquone/proguanil is active against the liver stage of P. falciparum malaria parasites and when used as a prophylactic agent it can be discontinued shortly after leaving malaria-endemic areas, offering a clear advantage for drug adherence.
Topics: Animals; Atovaquone; Drug Therapy, Combination; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil
PubMed: 16307498
DOI: 10.1586/14787210.3.6.849 -
Pathology, Research and Practice Aug 2021The poor outcomes in ovarian cancer necessitate new treatments. Strategies to interfere with oxidative phosphorylation have been recently highlighted for the treatment...
The poor outcomes in ovarian cancer necessitate new treatments. Strategies to interfere with oxidative phosphorylation have been recently highlighted for the treatment of ovarian tumors. Atovaquone, an approved antimicrobial drug, has demonstrated anti-cancer potential and ability in disrupting mitochondrial function. Here, we investigated the efficacy of atovaquone as single drug and its combination with cisplatin in ovarian cancer. We show that atovaquone at clinically achievable concentrations is active against ovarian cancer bulky and stem-cell like cells via inhibiting growth and colony formation, and inducing caspase-dependent apoptosis. In contrast, atovaquone either does not or inhibits normal cells in a less extent than in ovarian cancer cells. Mechanism studies using multiple independent approaches demonstrate that atovaquone acts on ovarian cancer cells via decreasing mitochondrial complex III which results in mitochondrial respiration inhibition, energy reduction and oxidative stress. In line with in vitro findings, atovaquone alone at non-toxic dose is effective in inhibiting ovarian cancer growth in vivo, and its combination with cisplatin is synergistic. Our study suggests that atovaquone is a promising candidate to the treatment of ovarian cancer. Our work also supports the notion that mitochondrial respiration is a therapeutic target in ovarian cancer.
Topics: Apoptosis; Atovaquone; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Humans; Mitochondria; Ovarian Neoplasms; Respiration
PubMed: 34174549
DOI: 10.1016/j.prp.2021.153529 -
Journal of Nanobiotechnology Oct 2021Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can...
BACKGROUND
Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia.
METHODS
We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment.
RESULTS
Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8 T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy.
CONCLUSIONS
Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.
Topics: Animals; Atovaquone; Cell Line, Tumor; Cells, Cultured; Drug Carriers; Immunotherapy; Mice; Mice, Inbred C57BL; Mice, SCID; Nanoparticles; Programmed Cell Death 1 Receptor; Smegmamorpha; Tumor Hypoxia; Tumor Microenvironment
PubMed: 34600560
DOI: 10.1186/s12951-021-01034-9 -
Emergencias : Revista de La Sociedad... Apr 2023
Topics: Humans; Proguanil; Atovaquone; Malaria, Falciparum; Drug Combinations; Antimalarials
PubMed: 37038945
DOI: No ID Found -
Viruses Aug 2023The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic...
The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.
Topics: Animals; Mice; SARS-CoV-2; COVID-19; Atovaquone; Endoribonucleases; Coronavirus OC43, Human
PubMed: 37766247
DOI: 10.3390/v15091841 -
Blood Advances Dec 2019Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated,...
Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML.
Topics: Activating Transcription Factor 4; Adolescent; Animals; Apoptosis; Atovaquone; Cell Line, Tumor; Cell Survival; Child; Child, Preschool; Disease Models, Animal; Female; Humans; Infant; Leukemia, Myeloid, Acute; Male; Mice; Mice, Knockout; Oxidative Phosphorylation; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 31856268
DOI: 10.1182/bloodadvances.2019000499 -
European Journal of Pharmaceutical... Jan 2018Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose...
Atovaquone in combination with proguanil hydrochloride, marketed as Malarone® tablets by GlaxoSmithKline (GSK), is prescribed for the treatment of malaria. High dose and poor bioavailability are the main hurdles associated with atovaquone oral therapy. The present study reports development of atovaquone nanoparticles, using in house designed and fabricated electrospraying equipment, and the assessment of bioavailability and therapeutic efficacy of the nanoparticles after oral administration. Solid nanoparticles of atovaquone were successfully produced by electrospraying and were characterized for particle size and flow properties. Differential Scanning Calorimetry, X-ray Diffraction, Fourier Transform Infrared Spectroscopy studies were also carried out. Atovaquone nanoparticles along with proguanil hydrochloride and a suitable wetting agent were filled in size 2 hard gelatin capsules. The formulation was compared with Malarone® tablets (GSK) and Mepron® suspension (GSK) in terms of in vitro release profile and in vivo pharmacokinetic studies. It showed 2.9-fold and 1.8-fold improved bioavailability in rats compared to Malarone® tablets and Mepron® suspension respectively. Therapeutic efficacy of the formulation was determined using modified Peter's 4-day suppressive tests and clinical simulation studies using Plasmodium berghei ANKA infected Swiss mice and compared to Malarone®. The developed formulation showed a 128-fold dose reduction in the modified Peter's 4-day suppressive tests and 32-fold dose reduction in clinical simulation studies. Given that only one capsule a day of developed formulation is required to be administered orally compared to 4 Malarone® tablets once a day and that too at a significantly reduced dose, this nanoparticle formulation will definitely reduce the side-effects of the treatment and is also likely to increase patient compliance.
Topics: Administration, Oral; Animals; Antimalarials; Atovaquone; Biological Availability; Drug Combinations; Malaria; Mice; Plasmodium berghei; Proguanil; Rats
PubMed: 28974387
DOI: 10.1016/j.ejps.2017.09.051 -
Molecular Cancer Therapeutics Oct 2019Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug,...
Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin, and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1, and c-Myc Efficacy of atovaquone was further evaluated in an tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, β-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.
Topics: Animals; Antiprotozoal Agents; Apoptosis; Atovaquone; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Female; Gene Silencing; Humans; Mice, Inbred BALB C; Paclitaxel; Proteasome Endopeptidase Complex; Receptor, ErbB-2; Signal Transduction; beta Catenin
PubMed: 31270151
DOI: 10.1158/1535-7163.MCT-18-1286 -
Travel Medicine and Infectious Disease 2020
Topics: Atovaquone; Drug Combinations; Female; Humans; Infant; Pregnancy; Proguanil; Retrospective Studies
PubMed: 31962169
DOI: 10.1016/j.tmaid.2020.101559