Drug Discovery Archives - Page 2 of 2 - Center for Tropical and Emerging Global Diseases

Probing the distinct chemosensitivity of Plasmodium vivax liver stage parasites and demonstration of 8-aminoquinoline radical cure activity in vitro

Donna Huber on October 7, 2021

Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade.

Steven P. Maher, Amélie Vantaux, Victor Chaumeau, Adeline C. Y. Chua, Caitlin A. Cooper, Chiara Andolina, Julie Péneau, Mélanie Rouillier, Zaira Rizopoulos, Sivchheng Phal, Eakpor Piv, Chantrea Vong, Sreyvouch Phen, Chansophea Chhin, Baura Tat, Sivkeng Ouk, Bros Doeurk, Saorin Kim, Sangrawee Suriyakan, Praphan Kittiphanakun, Nana Akua Awuku, Amy J. Conway, Rays H. Y. Jiang, Bruce Russell, Pablo Bifani, Brice Campo, François Nosten, Benoît Witkowski & Dennis E. Kyle. Sci Rep 11, 19905 (2021). https://doi.org/10.1038/s41598-021-99152-9

UGA researchers developing new models for malaria drug development and testing

Donna Huber on September 23, 2021

Chet Joyner and Dennis Kyle — CTEGD member Chet Joyner and CTEGD director Dennis Kyle receive a grant from the Bill & Melinda Gates Foundation for malaria drug development and testing

Two UGA researchers are working to make it easier to develop effective treatments for malaria, a disease that sickens millions worldwide and kills hundreds of thousands each year.

In tropical climates around the globe, malaria poses a grave risk to already vulnerable populations. In 2019, the World Health Organization estimated that there were 229 million clinical cases of malaria worldwide and 409,000 deaths, usually in children below the age of five.

Currently, developing and testing drugs for malaria requires scientists to work in areas where the disease is prevalent or to work with expensive, hard-to-source equipment. Chester Joyner, an Assistant Professor in the Center for Vaccines and Immunology, and Dennis Kyle, Professor of Infectious Diseases and Cellular Biology, are working to reduce those barriers to malaria drug testing and development.

Joyner and Kyle aim to establish systems that rely on equipment most researchers can obtain: a petri dish. If successful, Joyner says this new culture system will reduce costs and be distributed more easily to advance drug and vaccine research. The University of Georgia College of Veterinary Medicine received a grant for malaria drug development and testing from the Bill & Melinda Gates Foundation.

Worldwide, there are many malaria-causing parasites that result in varying degrees of illness. Joyner and Kyle’s research focuses on defeating one of the most challenging: Plasmodium vivax. Unlike many other malaria parasites, P. vivax can lie dormant in the livers of its hosts—allowing the infected to travel abroad completely unaware that they’re carrying a potentially deadly passenger.

“Most infections with P. vivax are not due to new infections,” says Joyner. “These infections come from this parasite activating and potentially causing disease and sustaining transmission.”

Malaria disproportionately affects the poorest communities in the world, creating a cycle of disease and poverty that current treatments have improved but been unable to stop. However, treating the dormant forms of P. vivax has been particularly challenging because they can cause more harm than good in at-risk populations like pregnant women and people with certain blood conditions.

“We want researchers to have access to technologies to study P. vivax and develop new approaches to control and eliminate this parasite,” Joyner explains.

This article first appeared at https://give.uga.edu/uga-researchers-developing-new-models-for-malaria-drug-development-and-testing/

Researchers to test drug candidates to treat malaria

Donna Huber on September 15, 2021

by Donna Huber

Though malaria was eliminated from the U.S. 70 years ago, the mosquito-borne disease caused by the Plasmodium parasite is still rampant in many parts of the world – nearly 40% of the world’s population is at risk of contracting it, and nearly 450,000 people die each year from it. With the rise of drug resistance, the current medical treatments aren’t enough to end this disease.

“Every drug treatment currently in use for malaria is showing resistance or reduced efficacy,” said Belen Cassera, a member of the University of Georgia’s Center for Tropical and Emerging Global Diseases. “Furthermore, there are very limited treatments for the most vulnerable – children and pregnant women. Over 60% of deaths are children under the age of 5.”

Cassera is co-leading the research team that recently received a $3.7 million grant from the National Institutes of Health to test two new drug candidates.

“These compounds are really promising as they are easy to synthesize, cheap, reliable, have a low toxicity profile, and kill the parasites fast,” said Cassera, associate professor in the Department of Biochemistry and Molecular Biology, part of the Franklin College of Arts and Sciences.

What’s unique about these compounds is that they can kill the parasite in three development stages in humans. Current treatments only target the blood stage, which is when clinical symptoms appear.

The life cycle of the Plasmodium parasite is complex. When an infected mosquito bites a person, just a small number of parasites – usually less than a hundred – are injected into the bite site and then travel to the liver, where they multiply in number to thousands. Once their numbers are sufficient enough, they invade the bloodstream and infect red blood cells.

When the number of parasites reaches 100 million, symptoms occur and some of the parasites develop into a sexual form, also known as the gametocyte stage. This is when symptoms occur. The sexual form is then transmitted back to the mosquito when the person is bitten again.

This complex life cycle makes it difficult to find a treatment that will eradicate the disease. Breaking the cycle of transmission between humans and mosquitos is key to accomplishing that goal. That’s why the team is excited about discovering compounds that can attack the parasite on multiple fronts.

“We are really a powerhouse team,” said Cassera. “We have a leading medicinal chemistry expert in Paul Carlier, the robust parasitology resources of UGA, and Max Totrov brings the machine-learning expertise to tie it all together.”

Cassera is a UGA Innovation Fellow, and she also credits the knowledge gained at UGA’s 2019 Innovation Bootcamp with helping her prepare a grant proposal that would be of particular interest to drug manufacturers.

Cassera has been working for several years to identify new drug candidates, along with Carlier, a professor in the Virginia Tech College of Science’s Department of Chemistry and director of the Virginia Tech Center for Drug Discovery, and Max Totrov, a computational chemist at Molsoft.

“We started working with the Malaria Box from Medicines for Malaria Venture, and the discoveries we made in basic malaria biochemistry and medicinal chemistry really springboarded us to a new level and led us in this new direction,” Cassera said.

Cassera is leading the testing of the new chemical variations of the antimalarial compounds prepared by Carlier for effectiveness in cellular and animal models.

“My lab will be looking at levels of toxicity, the potential for resistance, and how well they work both directly on the parasite and in infected mice,” she said. “We’ll be performing the studies for making the go/no-go decision for these compounds.”

A joint patent application for both drug candidates was recently filed, and the team is optimistic that their research will yield fast-acting candidates for advanced pre-clinical evaluation.

This story originally appeared at UGAResearch

Synthesis of Mono- and Bisperoxide-Bridged Artemisinin Dimers to Elucidate the Contribution of Dimerization to Antimalarial Activity

Donna Huber on April 1, 2021

During the past decade, artemisinin as an antimalarial has been in the spotlight, in part due to the Nobel Prize in Physiology or Medicine awarded to Tu Youyou. While many studies have been completed detailing the significant increase in activity resulting from the dimerization of natural product artemisinin, activity increases unaccounted for by the peroxide bridge have yet to be researched. Here we outline the synthesis and testing for antimalarial activity of artemisinin dimers in which the peroxide bridge in one-half of the dimer is reduced, resulting in a dimer with one active and one deactivated artemisinin moiety.

Cynthia L Lichorowic, Yingzhao Zhao, Steven P Maher, Vivian Padín-Irizarry, Victoria C Mendiola, Sagan T de Castro, Jacob A Worden, Debora Casandra, Dennis E Kyle, Roman Manetsch. ACS Infect Dis. 2021 Apr 1. doi: 10.1021/acsinfecdis.1c00066

Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae

Donna Huber on September 24, 2020

Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. Since repurposing drugs is an ideal strategy for orphan diseases, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 <1 μM) against N. fowleri (n = 19), A. castellanii (n = 12), and B. mandrillaris (n = 27) plus an additional 90 micromolar inhibitors. Of these, 113 inhibitors have never been reported to have activity against Naegleria, Acanthamoeba or Balamuthia. Rapid onset of action is important for new anti-amoeba drugs and we identified 19 compounds that inhibit N. fowleri in vitro within 24 hours (halofuginone, NVP-HSP990, fumagillin, bardoxolone, belaronib, and BPH-942, solithromycin, nitracrine, quisinostat, pabinostat, pracinostat, dacinostat, fimepinostat, sanguinarium, radicicol, acriflavine, REP3132, BC-3205 and PF-4287881). These compounds inhibit N. fowleri in vitro faster than any of the drugs currently used for chemotherapy. The results of these studies demonstrate the utility of phenotypic screens for discovery of new drugs for pathogenic free-living amoebae, including Acanthamoeba for the first time. Given that many of the repurposed drugs have known mechanisms of action, these compounds can be used to validate new targets for structure-based drug design.

Christopher A Rice, Beatrice L Colon, Emily Chen, Mitchell V Hull, Dennis E Kyle. PLoS Negl Trop Dis. 2020 Sep 24;14(9):e0008353. doi: 10.1371/journal.pntd.0008353.

New UGA Drug Discovery Core lab works to develop treatment of leading diseases

Donna Huber on November 8, 2017

Drug Discovery Center team — Members of the Drug Discovery Core steering committee in the new DDC laboratory (from left to right): Shelley Hooks, interim director of the Center for Drug Discovery and associate professor of pharmaceutical and biomedical sciences; Scott Pegan, chair of the steering committee and associate professor of pharmaceutical and biomedical sciences; Belen Cassera, associate professor of biochemistry and molecular biology; Kojo Mensa-Wilmot, professor and head of UGA’s cellular biology department and director of the Chemical Biology Group; and Brian Cummings, director of the Interdisciplinary Toxicology Program and professor of pharmaceutical and biomedical sciences.

Athens, Ga. – The University of Georgia has created the Drug Discovery Core laboratory, a campus-wide collaborative facility designed to hasten the development of therapeutic drugs for a number of major diseases.

A survey distributed to UGA researchers in 2016 identified chemical screening and toxicity profiling as the most critical needs for enhancing drug discovery research at UGA, and the DDC will address many of those needs for faculty working in infectious disease, regenerative medicine, cancer biology and other human health-focused disciplines.

Phase one of the new lab will allow for the curation, management and distribution of chemical libraries containing more than 50,000 compounds. The lab also will enable researchers to rapidly screen these chemical libraries in miniaturized models of various diseases using robotics and high-throughput signal detection. Finally, the lab will provide opportunities to identify potential toxicity of the compounds and determine if their chemical properties will allow them to be successfully delivered to patients. Additional capabilities, including pharmacokinetic characterization, genotoxicity and assay design, are under development.

“The most immediate outcome of the DDC lab will be to generate preliminary data from pilot chemical screens, which is necessary to secure large drug discovery grants from the National Institutes of Health to fund more advanced drug discovery research,” said Shelley Hooks, interim director of the Center for Drug Discovery and associate professor of pharmaceutical and biomedical science. “The longer-term goals of the lab are to discover and develop new drug candidates and chemical probes, as well as enhance training of graduate students in biotechnology.”

Creation of the DDC was initiated by Hooks in collaboration with Brian Cummings, director of the Interdisciplinary Toxicology Program and professor in the pharmaceutical and biomedical sciences department, and Scott Pegan, chair of the DDC steering committee and associate professor of pharmaceutical and biomedical sciences.

Sponsoring campus organizations include the College of Pharmacy, the College of Veterinary Medicine, the Office of Research, the Center for Tropical and Emerging Diseases and the Department of Cellular Biology.

The laboratory is located in Room 224 of the Wilson Building in the College of Pharmacy. For more information on capability, resources and access to the libraries and screening instruments, contact Pegan (spegan@uga.edu) or see cdd.rx.uga.edu.

Writer: Mickey Y. Montevideo
Contact: Shelley B. Hooks

Tag: Drug Discovery