publications Archives - Page 11 of 59 - Center for Tropical and Emerging Global Diseases

Polychlorinated cyclopentenes from a marine derived Periconia sp. (strain G1144)

Donna Huber on April 11, 2022

Studies on an organic extract of a marine fungus, Periconia sp. (strain G1144), led to the isolation of three halogenated cyclopentenes along with the known and recently reported rhytidhyester D; a series of spectrometric and spectroscopic techniques were used to elucidate these structures. Interestingly, two of these compounds represent tri-halogenated cyclopentene derivatives, which have been observed only rarely from Nature. The relative and absolute configurations of the compounds were established via mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, Mosher’s esters method, optical rotation and GIAO NMR calculations, including correlation coefficient calculations and the use of both DP4+ and dJ DP4 analyses. Several of the isolated compounds were tested for activity in anti-parasitic, antimicrobial, quorum sensing inhibition, and cytotoxicity assays and were shown to be inactive.

Kristóf B Cank, Robert A Shepherd, Sonja L Knowles, Manuel Rangel-Grimaldo, Huzefa A Raja, Zoie L Bunch, Nadja B Cech, Christopher A Rice, Dennis E Kyle, Joseph O Falkinham 3rd, Joanna E Burdette, Nicholas H Oberlies. Phytochemistry . 2022 Apr 11;113200. doi: 10.1016/j.phytochem.2022.113200

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

Donna Huber on March 31, 2022

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)

Donna Huber on March 30, 2022

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.

Parasite Powerhouse: a Review of the Toxoplasma gondii Mitochondrion

Donna Huber on March 21, 2022

Toxoplasma gondii is a member of the apicomplexan phylum, a group of single-celled eukaryotic parasites that cause significant human morbidity and mortality around the world. T. gondii harbors two organelles of endosymbiotic origin: a non-photosynthetic plastid, known as the apicoplast, and a single mitochondrion derived from the ancient engulfment of an α-proteobacterium. Due to excitement surrounding the novelty of the apicoplast, the T. gondii mitochondrion was, to a certain extent, overlooked for about two decades. However, recent work has illustrated that the mitochondrion is an essential hub of apicomplexan-specific biology. Development of novel techniques, such as cryo-electron microscopy, complexome profiling, and next-generation sequencing have led to a renaissance in mitochondrial studies. This review will cover what is currently known about key features of the T. gondii mitochondrion, ranging from its genome to protein import machinery and biochemical pathways. Particular focus will be given to mitochondrial features that diverge significantly from the mammalian host, along with discussion of this important organelle as a drug target.

Madelaine M. Usey, Diego Huet. J Eukaryot Microbiol. 2022 Mar 21;e12906. doi: 10.1111/jeu.12906.

Development and Introduction of the Filariasis Test Strip: A New Diagnostic Test for the Global Program to Eliminate Lymphatic Filariasis

Donna Huber on March 15, 2022

A key component to achieving the global goal of elimination of lymphatic filariasis (LF) is the availability of appropriate tools for disease mapping, monitoring, and surveillance. However, the development of these tools for a neglected disease such as LF can be a challenge. The lack of a commercial market and low familiarity with these diseases leave little incentive for diagnostic manufacturers to invest in this space. The Filarial Test Strip (FTS) development story provides a case study on how a multi-stakeholder, public-private partnership model facilitated the development, evaluation, and introduction of a new monitoring and surveillance tool for LF. This paper will reflect on the experience with the FTS and document the process from development of the target product profile to adoption and scale-up in country programs. Lessons learned from both the successes and challenges experienced during this process may help inform future efforts to develop and introduce new diagnostic or surveillance tools for neglected diseases.

Anastasia Pantelias, Jonathan D King, Patrick Lammie, Gary J Weil. Am J Trop Med Hyg. 2022 Mar 15;tpmd210990. doi: 10.4269/ajtmh.21-0990.

In Vivo Efficacy of SQ109 against Leishmania donovani, Trypanosoma spp. and Toxoplasma gondii and In Vitro Activity of SQ109 Metabolites

Donna Huber on March 14, 2022

SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including Leishmania and Trypanosoma cruzi spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of Leishmania, Trypanosoma spp. as well as Toxoplasma infection. In the T. cruzi mouse model, 80% of SQ109-treated mice survived at 40 days post-infection. Even though SQ109 did not cure all mice, these results are of interest since they provide a basis for future testing of combination therapies with the azole posaconazole, which acts synergistically with SQ109 in vitro. We also found that SQ109 inhibited the growth of Toxoplasma gondii in vitro with an IC₅₀ of 1.82 µM and there was an 80% survival in mice treated with SQ109, whereas all untreated animals died 10 days post-infection. Results with Trypanosoma brucei and Leishmania donovani infected mice were not promising with only moderate efficacy. Since SQ109 is known to be extensively metabolized in animals, we investigated the activity in vitro of SQ109 metabolites. Among 16 metabolites, six mono-oxygenated forms were found active across the tested protozoan parasites, and there was a ~6× average decrease in activity of the metabolites as compared to SQ109 which is smaller than the ~25× found with mycobacteria.

Kyung-Hwa Baek, Trong-Nhat Phan, Satish R Malwal, Hyeryon Lee, Zhu-Hong Li, Silvia N J Moreno, Eric Oldfield, Joo Hwan No. Biomedicines. 2022 Mar 14;10(3):670. doi: 10.3390/biomedicines10030670.

Insulin-like peptide 3 stimulates hemocytes to proliferate in anautogenous and facultatively autogenous mosquitoes

Donna Huber on March 8, 2022

Most mosquito species are anautogenous, which means they must blood feed on a vertebrate host to produce eggs, while a few are autogenous and can produce eggs without blood feeding. Egg formation is best understood in the anautogenous mosquito Aedes aegypti, where insulin-like peptides (ILPs), ovary ecdysteroidogenic hormone (OEH) and 20-hydroxyecdysone (20E) interact to regulate gonadotrophic cycles. Circulating hemocytes also approximately double in abundance in conjunction with a gonadotrophic cycle, but the factors responsible for stimulating this increase remain unclear. Focusing on Ae. aegypti, we determined that hemocyte abundance similarly increased in intact blood-fed females and decapitated blood-fed females that were injected with ILP3, whereas OEH, 20E or heat-killed bacteria had no stimulatory activity. ILP3 upregulated insulin-insulin growth factor signaling in hemocytes, but few genes – including almost no transcripts for immune factors – were differentially expressed. ILP3 also stimulated circulating hemocytes to increase in two other anautogenous (Anopheles gambiae and Culex quinquefasciatus) and two facultatively autogenous mosquitoes (Aedes atropalpus and Culex pipiens molestus), but had no stimulatory activity in the obligately autogenous mosquito Toxorhynchites amboinensis. Altogether, our results identify ILPs as the primary regulators of hemocyte proliferation in association with egg formation, but also suggest this response has been lost in the evolution of obligate autogeny.

Ellen O Martinson, Kangkang Chen, Luca Valzania, Mark R Brown, Michael R Strand. J Exp Biol. 2022 Mar 1;225(5):jeb243460. doi: 10.1242/jeb.243460.

The Peptide Hormone CNMa Influences Egg Production in the Mosquito Aedes aegypti

Donna Huber on February 25, 2022

Mosquito reproduction is regulated by a suite of hormones, many acting through membrane-bound receptor proteins. The Aedes aegypti G protein-coupled receptors AAEL024199 (AeCNMaR-1a) and AAEL018316 (AeCNMaR-1b) were identified as orthologs of the Drosophila melanogaster CNMa receptor (DmCNMaR). The receptor was duplicated early in the evolution of insects, and subsequently in Culicidae, into what we refer to as CNMaR-1a and CNMaR-1b. AeCNMaR-1a is only detected in male mosquito antennae while AeCNMaR-1b is expressed at high levels in mosquito ovaries. Using a heterologous cell assay, we determined that AeCNMa activates AeCNMaR-1a with a ~10-fold lower concentration than it does AeCNMaR-1b, though both receptors displayed half maximal effective concentrations of AeCNMa in the low nanomolar range. Finally, we show that injections of AeCNMa into blood-fed mated female Ae. aegypti resulted in fewer eggs laid.

Nia I Keyes-Scott, Aryan Lajevardi, Kyle R Swade, Mark R Brown, Jean-Paul Paluzzi, Kevin J Vogel. Insects. 2022 Feb 25;13(3):230. doi: 10.3390/insects13030230.

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

Donna Huber on February 24, 2022

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. https://doi.org/10.1021/acsmedchemlett.1c00697

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

Donna Huber on February 23, 2022

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.

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