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Tag: malaria

Characterization of β-Carboline Derivatives Reveals a High Barrier to Resistance and Potent Activity against Ring-Stage and DHA-Induced Dormant Plasmodium falciparum

Donna Huber on October 17, 2025

graphical abstract

Malaria, caused by Plasmodium falciparum, remains a major global health challenge, with an estimated 263 million new infections and 597,000 deaths annually. Increasing resistance to current antimalarial drugs underscores the urgent need for new therapeutics that target novel pathways in the parasite. We previously reported a novel class of β-carboline antimalarials, exemplified by PRC1584, which demonstrated a favorable oral pharmacokinetic profile, in vivo efficacy in Plasmodium berghei-infected mice, and no cross-resistance with other antimalarials in various P. falciparum strains. In this study, we demonstrate that PRC1584 exhibits a high resistance barrier and retains potent activity against fresh Ugandan P. falciparum isolates. PRC1584, along with its more potent analog PRC1697, demonstrated strong in vitro potency against both actively proliferating ring stages and dihydroartemisinin-induced dormant stages. Additionally, our study demonstrated that PfKelch13-C580Y mutation was associated with an increased susceptibility to PRC1584, whereas PfKelch13-R549T and Pfcoronin-R100 K-E107V mutations were not associated with this effect. These findings underscore the therapeutic potential of this new “irresistible” compound class, support a possible novel mechanism of action, and suggest the future development of novel ACTs active against resistant parasites by targeting DHA dormancy, an essential survival mechanism of P. falciparum.

Reagan S Haney, Joshua H Butler, Lyric A Wardlaw, Emilio F Merino, Victoria Mendiola, Caitlin A Cooper, Jopaul Mathew, Patrick K Tumwebaze, Philip J Rosenthal, Roland A Cooper, Dennis E Kyle, Zaira Rizopoulos, Delphine Baud, Stephen Brand, Maxim Totrov, Paul R Carlier, Maria Belen Cassera. ACS Infect Dis. 2025 Oct 17. doi: 10.1021/acsinfecdis.5c00714.

Benzo-ring modification on Malaria Box hit MMV008138: effects on antimalarial potency and microsomal stability

Donna Huber on August 15, 2025

graphical abstract

Tetrahydro-β-carboline 1 (MMV008138) controls growth of asexual blood-stage Plasmodium falciparum by inhibiting IspD, an enzyme in the MEP pathway for synthesis of a critical metabolite, isopentenyl pyrophosphate (IPP). We have previously investigated the structure activity relationship (SAR) of three of its four rings (B, C, and D). In this report we investigate the SAR of the benzo- (i.e. A-ring) of 1, with the goal of increasing its in vitro antimalarial potency and metabolic stability. As in our previous studies of the B- and C-ring substitution, extreme sensitivity to substitution was also seen in the benzo-ring. In total, 19 benzo-ring substitution variants of 1 were prepared. When tested against multidrug-resistant (Dd2 strain) P. falciparum, only three derivatives (20a, c, d) possessed asexual blood stage (ABS) activity with EC50 values within 3-fold of the parent. As hoped, one analog (20c) showed a marked improvement in microsomal stability. However, this improvement unfortunately did not improve plasma exposure relative to 1, and did not lead to oral efficacy in a mouse model of malaria.

Maryam Ghavami, Haibo Li, Lixuan Liu, Joshua H Butler, Sha Ding, Grant J Butschek, Reagan S Haney, R McAlister Council-Troche, R Justin Grams, Emilio F Merino, Jennifer M Davis, Maxim Totrov, Maria B Cassera, Paul R Carlier. RSC Med Chem. 2025 Aug 15. doi: 10.1039/d5md00439j.

Antimalarial spirooxindole alkaloids with a rare 6/5/5/6/6 polycyclic skeleton from the fungus Penicillium citrinum YSC-1 isolated from a medicinal plant

Donna Huber on August 5, 2025

graphical abstract

OSMAC (one strain many compounds) provides a convenient strategy to produce chemically diverse and novel natural products. In the study, the application of an OSMAC approach on a fungus Penicillium citrinum YSC-1 isolated from a medicinal plant Chloranthus japonicus, using different culture media, led to the isolation and identification of seven new spirooxindole alkaloids penicitrimicins A-G (1-7) with a rare 6/5/5/6/6 polycyclic skeleton, along with two known compounds (8-9). The new structures were characterized based on the comprehensive spectroscopic analyses, including 1D, 2D NMR and HRESIMS data. The absolute configurations of compounds 1-7 were determined by modified Mosher ester methodology, PGME derivatization, X-ray crystallographic analysis, and quantum chemical calculations. Biological evaluation revealed that these spirooxindole alkaloids exhibited good biocompatibility (<5 % hemolysis and > 80 % cell viability) while displaying obvious antimalarial activity against Plasmodium falciparum Dd2 strain, with EC50 values spanning 0.9-2.4 μM. Furthermore, stage-specific assays revealed that compound 5 displayed significant inhibitory effects on the developmental transition of asexual blood-stage parasites, effectively blocking their progression to subsequent lifecycle stages.

Pei-Qian Wu, Jun-Su Zhou, Leticia S Do Amaral, Maria B Cassera, Jian-Min Yue, Bin Zhou. Bioorg Chem. 2025 Aug 5:164:108825. doi: 10.1016/j.bioorg.2025.108825.

Kurup wins prestigious PATH award for groundbreaking malaria research

Donna Huber on June 10, 2025

Assistant Professor Samarchith “Sam” Kurup is the first UGA researcher to receive the Burroughs Wellcome Fund’s Investigators in Pathogenesis of Infectious Disease (PATH) award. Kurup studies the parasites that cause malaria and how they penetrate the body’s defenses, which could lead to more effective therapeutics. (Photo by Lauren Corcino)

Every year, malaria evades the immune defenses of nearly 250 million people. But Samarchith “Sam” Kurup is determined to outsmart the parasite before it strikes. Now, with the Burroughs Wellcome Fund’s prestigious Investigators in Pathogenesis of Infectious Disease (PATH) award in hand, his lab is one step closer.

Burroughs Wellcome recently announced its 2025 cohort of eight innovative scientists. Kurup is the first University of Georgia faculty member to receive this highly competitive award.

Growing up in India, Kurup saw malaria’s toll firsthand. That drove him to study parasites—first as a veterinarian, and then as a Ph.D. student. After completing training in veterinary medicine, he pursued his Ph.D. at UGA, studying another parasite that infects both humans and animals, Trypanosoma cruzi. He also began pairing his parasitology knowledge with immunology.

After graduating, Kurup returned as a postdoc to the study of Plasmodium, the parasite that causes malaria. In 2019, Kurup joined the faculty in the Franklin College of Arts and Sciences and the Center for Tropical and Emerging Global Diseases where he has established a robust research program.

“My lab is trying to understand how we, as hosts, fight malaria parasites in the liver,” said Kurup. “We know the liver cells have their own ‘home defense system’ and don’t have to call in other immune cells to handle the parasites. But somehow a few parasites are able to circumvent this defense system.”

In 2022, Kurup was awarded a five-year National of Institutes of Health grant to study how our liver cells target Plasmodium. Human malaria infection begins in what is called the liver stage of the parasite’s life cycle. After an infected mosquito bites a person, the parasite then travels to the liver where it replicates. While a person is not symptomatic at this point, the human immune system is already deploying its defenses. Kurup’s lab wants to understand why the human immune system is unable to fully clear the infection at this point.

“About 10% of the parasites are able to evade our immune responses within the hepatocytes,” said Kurup. “If we can figure out the parasite’s strategy, how they get through our defenses, then we have a chance of shutting them down completely.”

The Kurup lab has identified special proteins (which they call “exported effectors”) that the parasite releases. They believe these proteins help the parasite to slip past the human immune system. However, little is known about how they work.

“We want to find out what the parasite is targeting in the host cell,” said Kurup. “This would open up whole new doors in therapeutic research.”

This image shows a Plasmodium parasite (green) being surrounded and attacked by guanylate binding proteins (red), the host’s defense. The host cell nucleus is shown in blue. All of this action happens within the host’s liver cell, and Sam Kurup is trying to determine how the parasite is able to thwart such an attack. (Image courtesy of Kurup Lab)
This image shows a Plasmodium parasite (green) being surrounded and attacked by guanylate binding proteins (red), the host’s defense. The host cell nucleus is shown in blue. All of this action happens within the host’s liver cell, and Sam Kurup is trying to determine how the parasite is able to thwart such an attack. (Image courtesy of Kurup Lab)

Plasmodium falciparum is often resistant to current drug treatments. As the most widespread and lethal strain of malaria, it is critical to find new ways to treat the infection. Kurup believes that by targeting the malaria parasite in the liver, the disease can be stopped in its tracks.

The PATH award funds early career scientists to pursue cutting-edge research that may be considered too risky for traditional funding opportunities. The award to Kurup also comes with $505,000 in flexible research support over the next five years to identify the “exported effector” proteins, study their behavior, and explore how they interact with the host’s liver cells.

“In addition to being a recognition of the important work that we do as a team, this award is an endorsement to chasing bold ideas and having lofty goals,” Kurup said. “If we crack the parasite’s playbook, we could turn the tide against malaria.”

Regulatory T cell memory: implications for malaria

Donna Huber on April 23, 2025

Figure 1.Hypothetical model of memory Treg development. Activated Tregs, which proliferate in the acute phase of malaria, leave a memory Treg pool in mice and humans.

Regulatory T cells (Tregs) can persist as memory cells (mTregs) in both infectious and non-infectious settings. However, their functional behavior, phenotypic stability, and suppressive properties upon antigen re-exposure remain poorly understood. Emerging evidence suggests that mTregs exhibit enhanced proliferation and suppressive capacity upon re-encountering the same antigen, a feature that may be critical in recurrent infections such as malaria. In malaria, Tregs are known to modulate immune responses and influence acute disease outcomes, suggesting that mTreg recall may play a significant role in long-term immunity. This review explores the biology of Treg memory, with a focus on malaria, and examines the immunological implications of maintaining a suppressive mTreg population in malaria immunity.

Nana Appiah Essel Charles-Chess, Samarchith P Kurup. J Immunol. 2025 Apr 23:vkaf067. doi: 10.1093/jimmun/vkaf067

Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria

Donna Huber on March 25, 2025

graphical abstractPlasmodium parasites undergo development and replication within hepatocytes before infecting erythrocytes and initiating clinical malaria. Although type I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1-mediated disruption of the PV activates the caspase-1 inflammasome, inducing pyroptosis to remove infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium, with their pharmacologic or genetic inhibition leading to profound malarial susceptibility in vivo. In addition to identifying IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, our study also extends the understanding of how non-immune cells are integral to protective immunity against malaria.

Camila Marques-da-Silva, Clyde Schmidt-Silva, Carson Bowers, Nana Appiah Essel Charles-Chess, Cristina Samuel, Justine C Shiau, Eui-Soon Park, Zhongyu Yuan, Bae-Hoon Kim, Dennis E Kyle, John T Harty, John D MacMicking, Samarchith P Kurup. Cell Host Microbe. 2025 Mar 25:S1931-3128(25)00091-5. doi: 10.1016/j.chom.2025.03.008.

Stereospecific Resistance to N2-Acyl Tetrahydro-β-carboline Antimalarials Is Mediated by a PfMDR1 Mutation That Confers Collateral Drug Sensitivity

Donna Huber on January 14, 2025

Half the world’s population is at risk of developing a malaria infection, which is caused by parasites of the genus Plasmodium. Currently, resistance has been identified to all clinically available antimalarials, highlighting an urgent need to develop novel compounds and better understand common mechanisms of resistance. We previously identified a novel tetrahydro-β-carboline compound, PRC1590, which potently kills the malaria parasite. To better understand its mechanism of action, we selected for and characterized resistance to PRC1590 in Plasmodium falciparum. Through in vitro selection of resistance to PRC1590, we have identified that a single-nucleotide polymorphism on the parasite’s multidrug resistance protein 1 (PfMDR1 G293V) mediates resistance to PRC1590. This mutation results in stereospecific resistance and sensitizes parasites to other antimalarials, such as mefloquine, quinine, and MMV019017. Intraerythrocytic asexual stage specificity assays have revealed that PRC1590 is most potent during the trophozoite stage when the parasite forms a single digestive vacuole (DV) and actively digests hemoglobin. Moreover, fluorescence microscopy revealed that PRC1590 disrupts the function of the DV, indicating a potential molecular target associated with this organelle. Our findings mark a significant step in understanding the mechanism of resistance and the mode of action of this emerging class of antimalarials. In addition, our results suggest a potential link between resistance mediated by PfMDR1 and PRC1590’s molecular target. This research underscores the pressing need for future research aimed at investigating the intricate relationship between a compound’s chemical scaffold, molecular target, and resistance mutations associated with PfMDR1.

Emily K Bremers, Joshua H Butler, Leticia S Do Amaral, Emilio F Merino, Hanan Almolhim, Bo Zhou, Rodrigo P Baptista, Maxim Totrov, Paul R Carlier, Maria Belen Cassera. ACS Infect Dis. 2025 Jan 14. doi: 10.1021/acsinfecdis.4c01001.