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Tag: malaria

Fagbami named 2022 Burroughs Wellcome Fund PDEP Fellow

postdoctoral fellow Lola Fagbami
UGA’s Lọla Fagbami, winner of a Burroughs Wellcome Fund 2022 Postdoctoral Diversity Enrichment Program fellowship, is a native of Lagos, Nigeria, who relocated to the United States with her family in the late 1990s. She is passionate about expanding scientific literacy through outreach and mentoring as well as refuting chemophobia—the fear of or aversion to chemicals and chemistry. (Photo by Lauren Corcino)

Lọla Fagbami, a postdoctoral research associate at UGA, has been awarded a Burroughs Wellcome Fund 2022 Postdoctoral Diversity Enrichment Program fellowship.

Fagbami, UGA’s first PDEP Fellow, conducts research on the human malaria parasite Plasmodium falciparum at the Center for Tropical and Emerging Global Diseases. She works with Vasant Muralidharan, associate professor of cellular biology in the Franklin College of Arts and Sciences, who nominated her for the award.

“Dr. Fagbami has excellent training in metabolomics, mass spectrometry and Plasmodium drug discovery. Her exceptional work as a graduate student has shown how human malaria-causing parasites use metabolic adaptation to induce antimalarial drug resistance. Dr. Fagbami is a fearless, highly intelligent, accomplished and outstanding scientist who will be a leader in our field,” Muralidharan wrote in his nomination letter.

“Her research project addresses a major gap in the field that has enormous implications for malaria elimination and eradication efforts,” he added.

The PDEP award provides $60,000 over three years to support career-development activities for historically excluded minority postdoctoral fellows pursuing academic careers in biomedical or medical research, according to the Burroughs Wellcome Fund.

“This award is an investment in me as a scientist and leader and will help advance my career to the next level,” Fagbami said. “I am excited to join the extraordinary community of PDEP scholars and also connect with program alumni who have successfully made the transition to research independence.”

Fagbami earned a B.S. in chemistry at Emory University, an M.B.S. and an M.P.H. in health policy at Rutgers University, and a Ph.D. in chemical biology at Harvard University.

Polymorphic Molecular Signatures in Variable Regions of the Plasmodium falciparum var2csa DBL3x Domain Are Associated with Virulence in Placental Malaria

The Plasmodium falciparum protein VAR2CSA allows infected erythrocytes to accumulate within the placenta, inducing pathology and poor birth outcomes. Multiple exposures to placental malaria (PM) induce partial immunity against VAR2CSA, making it a promising vaccine candidate. However, the extent to which VAR2CSA genetic diversity contributes to immune evasion and virulence remains poorly understood. The deep sequencing of the var2csa DBL3X domain in placental blood from forty-nine primigravid and multigravid women living in malaria-endemic western Kenya revealed numerous unique sequences within individuals in association with chronic PM but not gravidity. Additional analysis unveiled four distinct sequence types that were variably present in mixed proportions amongst the study population. An analysis of the abundance of each of these sequence types revealed that one was inversely related to infant gestational age, another was inversely related to placental parasitemia, and a third was associated with chronic PM. The categorization of women according to the type to which their dominant sequence belonged resulted in the segregation of types as a function of gravidity: two types predominated in multigravidae whereas the other two predominated in primigravidae. The univariate logistic regression analysis of sequence type dominance further revealed that gravidity, maternal age, placental parasitemia, and hemozoin burden (within maternal leukocytes), reported a lack of antimalarial drug use, and infant gestational age and birth weight influenced the odds of membership in one or more of these sequence predominance groups. Cumulatively, these results show that unique var2csa sequences differentially appear in women with different PM exposure histories and segregate to types independently associated with maternal factors, infection parameters, and birth outcomes. The association of some var2csa sequence types with indicators of pathogenesis should motivate vaccine efforts to further identify and target VAR2CSA epitopes associated with maternal morbidity and poor birth outcomes.

Eldin Talundzic, Stephen Scott, Simon O Owino, David S Campo, Naomi W Lucchi, Venkatachalam Udhayakumar, Julie M Moore, David S Peterson. Pathogens. 2022 Apr 28;11(5):520. doi: 10.3390/pathogens11050520

Improving in vitro continuous cultivation of Plasmodium cynomolgi, a model for P. vivax

The absence of a routine continuous in vitro cultivation method for Plasmodium vivax, an important globally distributed parasite species causing malaria in humans, has restricted investigations to field and clinical sampling. Such a method has recently been developed for the Berok strain of P. cynomolgi, a parasite of macaques that has long been used as a model for P. vivax, as these two parasites are nearly indistinguishable biologically and are genetically closely related. The availability of the P. cynomolgi Berok in routine continuous culture provides for the first time an opportunity to conduct a plethora of functional studies. However, the initial cultivation protocol proved unsuited for investigations requiring extended cultivation times, such as reverse genetics and drug resistance. Here we have addressed some of the critical obstacles to this, and we propose a set of modifications that help overcome them.

Peter Christensen, Annie Racklyeft, Kurt E Ward, Jessica Matheson, Rossarin Suwanarusk, Adeline C Y Chua, Osamu Kaneko, Htin Lin Aung, Laurent Rénia, Nadia Amanzougaghene, Victor Magneron, Julien Lemaitre, Roger Le Grand, Dennis Kyle, Pablo Bifani, Gregory M Cook, Georges Snounou, Bruce Russell. Parasitol Int. 2022 Apr 22;89:102589. doi: 10.1016/j.parint.2022.102589. Online ahead of print.

Alkyne modified purines for assessment of activation of Plasmodium vivax hypnozoites and growth of pre-erythrocytic and erythrocytic stages in Plasmodium spp

Graphical Abstract

Malaria is a major global health problem which predominantly afflicts developing countries. Although many antimalarial therapies are currently available, the protozoan parasite causing this disease, Plasmodium spp., continues to evade eradication efforts. One biological phenomenon hampering eradication efforts is the parasite’s ability to arrest development, transform into a drug-insensitive form, and then resume growth post-therapy. Currently, the mechanisms by which the parasite enters arrested development, or dormancy, and later recrudesces or reactivates to continue development, are unknown and the malaria field lacks techniques to study these elusive mechanisms. Since Plasmodium spp. salvage purines for DNA synthesis, we hypothesized that alkyne-containing purine nucleosides could be used to develop a DNA synthesis marker which could be used to investigate mechanisms behind dormancy. Using copper-catalyzed click chemistry methods, we observe incorporation of alkyne modified adenosine, inosine, and hypoxanthine in actively replicating asexual blood stages of Plasmodium falciparum and incorporation of modified adenosine in actively replicating liver stage schizonts of Plasmodium vivax. Notably, these modified purines were not incorporated in dormant liver stage hypnozoites, suggesting this marker could be used as a tool to differentiate replicating and non-replicating liver forms and, more broadly, as a tool for advancing our understanding of Plasmodium dormancy mechanisms.

Alona Botnar, Grant Lawrence, Steven P Maher, Amélie Vantaux, Benoît Witkowski, Justine C Shiau, Emilio F Merino, David De Vore, Christian Yang, Cameron Murray, Maria B Cassera, James W Leahy, Dennis E Kyle. Int J Parasitol. 2022 Apr 18;S0020-7519(22)00066-2. doi: 10.1016/j.ijpara.2022.03.003.

Anopheles gambiae strain (Ag55) cultured cells originated from Anopheles coluzzii and are phagocytic with hemocyte-like gene expression

Anopheles gambiae and Anopheles coluzzii are closely related species that are predominant vectors of malaria in Africa. Recently, A. gambiae form M was renamed A. coluzzii and we now conclude on the basis of a diagnostic PCR-restriction fragment length polymorphism assay that Ag55 cells were derived from A. coluzzii. We established an Ag55 cell transcriptome, and KEGG pathway analysis showed that Ag55 cells are enriched in phagosome pathway transcripts. The Ag55 transcriptome has an abundance of specific transcripts characteristic of mosquito hemocytes. Functional E. coli bioparticle uptake experiments visualized by fluorescence microscopy and confocal microscopy and quantified by flow cytometry establish the phagocytic competence of Ag55 cells. Results from this investigation of Ag55 cell properties will guide researchers in the use and engineering of the Ag55 cell line to better enable investigations of Plasmodium, other microbes, and insecticidal toxins. Graphical abstract: Anopheles gambiae cultured Ag55 cells originated from Anopheles coluzzi, have a hemocyte-like transcriptome and are phagocytic. This article is protected by copyright. All rights reserved.

Ruchir Mishra, Gang Hua, Ujwal R Bagal, Donald E Champagne, Michael J Adang. Insect Sci. 2022 Mar 31. doi: 10.1111/1744-7917.13036.

Metabolic, Pharmacokinetic, and Activity Profile of the Liver Stage Antimalarial (RC-12)

The catechol derivative RC-12 (WR 27653) (1) is one of the few non-8-aminoquinolines with good activity against hypnozoites in the gold-standard Plasmodium cynomolgi-rhesus monkey (Macaca mulatta) model, but in a small clinical trial, it had no efficacy against Plasmodium vivax hypnozoites. In an attempt to better understand the pharmacokinetic and pharmacodynamic profile of 1 and to identify potential active metabolites, we now describe the phase I metabolism, rat pharmacokinetics, and in vitro liver-stage activity of 1 and its metabolites. Compound 1 had a distinct metabolic profile in human vs monkey liver microsomes, and the data suggested that the O-desmethyl, combined O-desmethyl/N-desethyl, and N,N-didesethyl metabolites (or a combination thereof) could potentially account for the superior liver stage antimalarial efficacy of 1 in rhesus monkeys vs that seen in humans. Indeed, the rate of metabolism was considerably lower in human liver microsomes in comparison to rhesus monkey microsomes, as was the formation of the combined O-desmethyl/N-desethyl metabolite, which was the only metabolite tested that had any activity against liver-stage P. vivax; however, it was not consistently active against liver-stage P. cynomolgi. As 1 and all but one of its identified Phase I metabolites had no in vitro activity against P. vivax or P. cynomolgi liver-stage malaria parasites, we suggest that there may be additional unidentified active metabolites of 1 or that the exposure of 1 achieved in the reported unsuccessful clinical trial of this drug candidate was insufficient to kill the P. vivax hypnozoites.

Yuxiang Dong, Yogesh Sonawane, Steven P Maher, Anne-Marie Zeeman, Victor Chaumeau, Amélie Vantaux, Caitlin A Cooper, Francis C K Chiu, Eileen Ryan, Jenna McLaren, Gong Chen, Sergio Wittlin, Benoît Witkowski, François Nosten, Kamaraj Sriraghavan, Dennis E Kyle, Clemens H M Kocken, Susan A Charman, Jonathan L Vennerstrom. ACS Omega. 2022 Mar 30;7(14):12401-12411. doi: 10.1021/acsomega.2c01099.

Enantiopure Benzofuran-2-carboxamides of 1-Aryltetrahydro-β-carbolines Are Potent Antimalarials In Vitro

The tetrahydro-β-carboline scaffold has proven fertile ground for the discovery of antimalarial agents (e.g., MMV008138 (1) and cipargamin (2)). Similarity searching of a publicly disclosed collection of antimalarial hits for molecules resembling 1 drew our attention to N2-acyl tetrahydro-β-carboline GNF-Pf-5009 ((±)-3b). Compound purchase, “analog by catalog”, and independent synthesis of hits indicated the benzofuran-2-yl amide portion was required for in vitro efficacy against P. falciparum. Preparation of pure enantiomers demonstrated the pharmacological superiority of (R)-3b. Synthesis and evaluation of D- and F-ring substitution variants and benzofuran isosteres indicated a clear structure-activity relationship. Ultimately (R)-3b was tested in Plasmodium berghei-infected mice; unfavorable physicochemical properties may be responsible for the lack of oral efficacy.

Hanan Almolhim, Sha Ding, Joshua H Butler, Emily K Bremers, Grant J Butschek, Carla Slebodnick, Emilio F Merino, Zaira Rizopoulos, Maxim Totrov, Maria B Cassera, Paul R Carlier. ACS Med. Chem. Lett. 2022, 13, 3, 371–376.

Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.

Jopaul Mathew, Sha Ding, Kevin A Kunz, Emily E Stacy, Joshua H Butler, Reagan S Haney, Emilio F Merino, Grant J Butschek, Zaira Rizopoulos, Maxim Totrov, Maria B Cassera, Paul R Carlier. ACS Med Chem Lett. 2022 Feb 23;13(3):365-370. doi: 10.1021/acsmedchemlett.1c00663.

Activity-based Crosslinking to Identify Substrates of Thioredoxin-domain Proteinsin Malaria Parasites

Malaria remains a major public health issue, infecting nearly 220 million people every year. The spread of drug-resistant strains of Plasmodium falciparum around the world threatens the progress made against this disease. Therefore, identifying druggable and essential pathways in P. falciparum parasites remains a major area of research. One poorly understood area of parasite biology is the formation of disulfide bonds, which is an essential requirement for the folding of numerous proteins. Specialized chaperones with thioredoxin (Trx) domains catalyze the redox functions necessary for breaking incorrect and forming correct disulfide bonds in proteins. Defining the substrates of these redox chaperones is difficult and immunoprecipitation based assays cannot distinguish between substrates and interacting partners. Further, the substrate or client interactions with the redox chaperones are usually transient in nature. Activity based crosslinkers that rely on the nucleophilic cysteines on Trx domains and the disulfide bond forming cysteines on clients provide an easily scalable method to trap and identify the substrates of Trx-domain containing chaperones. The cell permeable crosslinker divinyl sulfone (DVSF) is active only in the presence of nucleophilic cysteines in proteins and, therefore, traps Trx domains with their substrates, as they form mixed disulfide bonds during the course of their catalytic activity. This allows the identification of substrates that rely on Trx activity for their folding, as well as discovering small molecules that interfere with Trx domain activity. Graphic abstract: Identification of thioredoxin domain substrates via divinylsulfone crosslinking and immunoprecipitation-mass spectrometry.

David W Cobb, Grace S Woods, Vasant Muralidharan. Bio Protoc. 2022 Feb 20;12(4):e4322. doi: 10.21769/BioProtoc.4322.

Structure-activity and structure-property relationship studies of spirocyclic chromanes with antimalarial activity

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.

Iredia D Iyamu, Yingzhao Zhao, Prakash T Parvatkar, Bracken F Roberts, Debora R Casandra, Lukasz Wojtas, Dennis E Kyle, Debopam Chakrabarti, Roman Manetsch. Bioorg Med Chem. 2022 Jan 14;57:116629. doi: 10.1016/j.bmc.2022.116629.