Breaking News
October 20, 2018 - Mad Cow disease found on Aberdeenshire farm
October 20, 2018 - Study identifies factors associated with prescription opioid misuse among students
October 20, 2018 - Scientists uncover key regulator of mTORC1 in cancer growth
October 20, 2018 - Pounds Regained After Weight-Loss Op Can Tell Your Doc a Lot
October 20, 2018 - Sending parents letters to fight childhood obesity doesn’t work
October 20, 2018 - Supervised aerobic exercise can support major depression treatment
October 20, 2018 - Mindfulness-based program effective for reducing stress in infertile women
October 20, 2018 - Molecule capable of halting and reverting neurodegeneration caused by Parkinson’s disease identified
October 20, 2018 - Midazolam-mediated alterations of PER2 expression may have functional consequences during myocardial ischemia
October 20, 2018 - Sweat bees are ideal for studying the genes underlying social behavior
October 20, 2018 - Weight loss success associated with brain areas involved in self-control
October 20, 2018 - KHN’s ‘What the Health?’ Republicans’ preexisting political problem
October 20, 2018 - Research provides a more complete picture of suffering caused by terrorist attacks
October 20, 2018 - Eradicating Helicobacter pylori infections may be a key treatment for Parkinson’s disease
October 20, 2018 - Breast Cancer as a Dynamic Disease
October 20, 2018 - University of Pittsburgh wins NSF grant for big data research to prevent complications from anesthesia
October 20, 2018 - Skin-to-skin contact may promote attachment between parents and preterm infants
October 20, 2018 - Recommendations Developed to Verify NGT Placement in Children
October 20, 2018 - Weight loss can be boosted fivefold thanks to novel mental imagery technique
October 20, 2018 - Children with autism are more likely to be overweight, obese
October 20, 2018 - Nurses making conscientious objections to ethically-relevant policies lack support
October 20, 2018 - Prion strain diversity may be greater than previously thought
October 20, 2018 - Antidepressant treatment may lead to improvements in sleep quality of patients with depression
October 20, 2018 - Study reports increased risk of death in children with inflammatory bowel disease
October 20, 2018 - Number of Autism Genes Now Tops 100
October 20, 2018 - Total diet replacement programmes are effective for treating obesity
October 20, 2018 - CLARIOstar used for fluorescence measurements on CSIRO’s purpose-built research vessel
October 20, 2018 - People with more copies of AMY1 gene digest starchy carbohydrates faster
October 20, 2018 - Case Comprehensive Cancer Center wins NIH grant to study health disparities
October 20, 2018 - Newly discovered compound shows potential for treating Parkinson’s disease
October 20, 2018 - High rate of non-adherence to hormonal therapy found among premenopausal early breast cancer patients
October 20, 2018 - Immunotherapy medicine found to be effective in treating uveitis
October 20, 2018 - The Pistoia Alliance Calls for Greater Collaboration to Realise Benefits of Innovation and Announces Winners of the 2018 President’s Startup Challenge
October 20, 2018 - Female internists consistently earn less than men
October 20, 2018 - Stanford team looks at dangers of teens’ vaping habits
October 20, 2018 - New approach to understanding cancers will accelerate development of better treatments
October 20, 2018 - LJI and UC San Diego awarded $ 4.5 million as part of NCI’s Cancer Moonshot initiative
October 20, 2018 - School-based HPV vaccination did not increase risky sexual behaviors among adolescent girls
October 20, 2018 - Eye discovery to pave way for more successful corneal transplants
October 20, 2018 - New analysis examines the importance of location in the opioid crisis
October 20, 2018 - Green filters increase reading speed for children with dyslexia
October 19, 2018 - Bariatric Sx Cuts Macrovascular Complications in Obesity, T2DM
October 19, 2018 - Better assessments for early age-related macular degeneration
October 19, 2018 - Visible and valued: Stanford Medicine’s first-ever LGBTQ+ Forum | News Center
October 19, 2018 - Understanding of metal-free enzymes used by bacteria could lead to new effective antibiotics
October 19, 2018 - Beckman Coulter Life Sciences announces new research-focused website
October 19, 2018 - Study finds link between refined soluble fibers, gut microbiota and liver cancer
October 19, 2018 - Social media reduces risk of depression among seniors with pain
October 19, 2018 - Newly developed synthetic DNA molecule may one day be used as ‘vaccine’ for prostate cancer
October 19, 2018 - Preoperative weight loss may not provide health benefits after surgery
October 19, 2018 - U.S. Birth Rates Continue to Drop as Age of New Moms Rises
October 19, 2018 - New technology can keep an eye on babies’ movements in the womb
October 19, 2018 - Juul e-cigarettes pose addiction risk for young users | News Center
October 19, 2018 - Gene sequencing reveals crucial molecular aspects of Trypanosoma brucei
October 19, 2018 - New DNA vaccine strategy protects mice against lethal challenge by multiple H3N2 viruses
October 19, 2018 - Study shows close link between cytokine interleukin-1ß and obesity-promoted colon cancer
October 19, 2018 - Muscle mass plays a critical role in health, shows research
October 19, 2018 - Study finds undiagnosed prediabetes in many infertile men
October 19, 2018 - The Current issue of “The view from here” is concerned with Nanotherapeutic strategies
October 19, 2018 - Delay in replacing the Pap smear with HPV screening is costing lives
October 19, 2018 - Physicians battle pediatric diseases of ear, nose, throat in Zimbabwe | News Center
October 19, 2018 - Researchers investigate why some cancers affect only young women
October 19, 2018 - Drugmakers funnel millions to lawmakers; a few dozen get $100,000-plus
October 19, 2018 - Unselfish people tend to have more children and receive higher salaries
October 19, 2018 - New findings reveal potential cellular players in tumor microenvironment
October 19, 2018 - Study reveals impact of Juul use on teenagers and young adults
October 19, 2018 - Green leafy vegetables could help reduce macular degeneration risk
October 19, 2018 - Some countries take more time for reimbursement decisions on new cancer drugs
October 19, 2018 - Human brain cell transplant offers insights into neurological conditions
October 19, 2018 - Parental education associated with increased family health care spending
October 19, 2018 - New statistical method estimates long- and short-term risk of recurrence of breast cancer in US women
October 19, 2018 - Father’s exposure to nicotine may cause cognitive deficits in descendants
October 19, 2018 - Could we prevent Alzheimer’s disease by treating herpes?
October 19, 2018 - Nurse-led care can be more successful in managing gout
October 19, 2018 - Trump administration, pharma exchange verbal volleys on drug-price transparency
October 19, 2018 - Duke researchers find way to detect blood doping in athletes
October 19, 2018 - Many primary care doctors are still prescribing sedative drugs for older adults
October 19, 2018 - Finger length can predict sexuality in women say researchers
October 19, 2018 - Study finds differences in side-effects experienced by male and female OG cancer patients
October 19, 2018 - Dysfunction of single gene leads to miscarriages
New laboratory-synthesized molecule appears to fight malaria effectively

New laboratory-synthesized molecule appears to fight malaria effectively

image_pdfDownload PDFimage_print

A novel laboratory-synthesized molecule based in natural compounds found in marine gliding bacteria – known as marinoquinolines – is a strong candidate for the development of a new antimalarial drug.

In tests, the molecule proved capable of killing even the strain that resists conventional antimalarials. The molecule displays low toxicity and high selectivity, acting only on the parasite and not on other cells of the host organism.

The molecule was developed in Brazil at the Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by the São Paulo Research Foundation – FAPESP. The researchers tested the molecule in strains cultured in vitro as well as in mice using Plasmodium berghei, since mice is immune to infection by Plasmodium falciparum, which causes the most aggressive type of malaria.

“In mice, the number of parasites in the bloodstream (parasitemia) had fallen 62% by the fifth day of the test. After 30 days, all the mice given doses of the molecule were still alive,” said Rafael Guido, a professor at the University of São Paulo’s São Carlos Physics Institute (IFSC-USP).

Guido co-authors an article published in the Journal of Medicinal Chemistry, on which the researchers describe the molecule’s inhibitory action in the blood and liver stages of the parasite’s asexual cycle, which is responsible for the signs and symptoms of the disease.

Potentializing the molecule’s pharmacological activity

Marinoquinolines were first isolated from marine gliding bacteria and, when discovered, were evaluated for activity against malaria, Chagas disease and tuberculosis. However, the natural products exhibited only weak to moderate activity against these pathogens.

“The core of these molecules, known as pyrroloquinoline [which contains 3H-pyrrolo[2,3-c]quinoline], drew our attention. This is a rare structure among natural products and is rarely discussed in the scientific literature,” said Carlos Roque Duarte Correia, a professor at the University of Campinas’s Chemistry Institute (IQ-UNICAMP) and principal investigator at the FAPESP center.

In 2012, the research group published a description of one of the first molecules synthesized from natural marinoquinolines.

“During the synthesis procedure, we realized the huge pharmacological potential of these molecules,” Guido said. “We then made new structural modifications to the pyrroloquinoline portion using efficient catalytic processes, and from the structure obtained, we created a new molecule with hundreds of times more firepower against P. falciparum and no increase in toxicity.”

Starved to death

The molecular mechanisms of action are not yet fully understood, but one of them is clearly hemozoin metabolism, a classic pathway for inhibiting the parasite.

The strategy consists of maintaining low levels of hemozoin, which is toxic to the parasite. Infection of the host begins in the red blood cells, as the hemoglobin they contain is the only source of energy for the parasite. Hemoglobin contains heme groups, which are highly toxic to the parasite in their free form (when separated from hemoglobin).

As the parasite has evolved, it has developed a mechanism that polymerizes heme groups to eliminate their toxicity. “This strategy for obtaining energy without toxicity is like sweeping dust under the carpet. The heme group stays there, but in a polymerized insoluble form that isn’t toxic to the parasite,” Guido said.

Among other mechanisms, the molecule developed by the CIBFar group of researchers inhibits this polymerization so the parasite is killed by the heme group.

“The molecule prevents formation of the polymer hemozoin, which the parasite has created to rid itself of the heme group’s toxicity. If you prevent hemozoin formation, you kill the parasite,” said Célia Regina Garcia, a professor in the University of São Paulo’s Pharmaceutical Science School (FCF-USP) and a coauthor of the article. Garcia partnered with CIBFar on the project and was responsible for testing the molecule’s mechanisms of action against the parasite.

Drug-resistant strains

Another indication that the marinoquinoline derivative is a promising drug candidate is the finding that it kills strains resistant to the three main antimalarial drugs, namely, chloroquine, pyrimethamine and sulfadoxine.

“Chloroquine is no longer used much to treat falciparum malaria, which accounts for the severest cases and most deaths from the disease,” Garcia said. “The same is expected of artemisinin, which is still the main antimalarial and still effective, but its days are numbered because of resistance. The drug-resistant strains are spreading throughout Asia. Hence, there is a worldwide concern to develop drugs for malaria. I believe Brazil has the potential to lead in this area.”

Malaria kills some 445,000 people each year, according to the World Health Organization (WHO). “If the number of deaths is so high while we have an effective drug, it will be even higher in future if we don’t develop new drugs,” Guido said. “Malaria is the world’s deadliest parasitic disease, even with the relatively effective treatment we currently have.”

Next steps

According to Duarte Correia, the first 50 molecules developed from marinoquinolines were tested in the FAPESP-supported study. “This work hasn’t ended with this publication. We’re still developing other compounds,” he said.

The researchers are also characterizing the potential of this class to treat malaria caused by P. vivax, the most prevalent form in Brazil and are developing the pharmacokinetic part of the project (how drugs move through the organism).

“If the pharmokinetic properties, especially solubility, absorption, distribution, metabolism and excretion, aren’t adequate, the compound can build up in the organism and become toxic to the patient, making it inappropriate for treatment. After completing this step, we plan to perform preclinical and clinical trials,” Guido said.

Source:

http://agencia.fapesp.br/new-molecule-considered-promising-antimalarial-candidate-/28400/

Tagged with:

About author

Related Articles