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Tag: Belen Cassera

Belen Cassera named parasitology section editor for Current Clinical Microbiology Reports

Donna Huber on July 8, 2021

Last summer, biochemistry associate professor and Center for Tropical and Emerging Global Diseases member Belen Cassera was named the parasitology section editor for Current Clinical Microbiology Reports and has produced her first issue of reviews.

Before former Editor-in-Chief Alan Hudson from Wayne State University School of Medicine stepped down, he recruited Cassera based on a recommendation from Robert Cramer at the Geisel School of Medicine. She met Cramer during an NIH study section.

“Networking is really important if you want to get involved in the editorial side of academic journals,” said Cassera.

In addition to participating in study sections and attending conferences, participating in the peer-review process at journals can also help get your name out there, particularly for senior trainees. She believes that having senior trainees review scientific articles is an important teaching tool.

“Reviewing papers can enhance your own critical thinking,” said Cassera. “Can you ask questions to improve the study or see something missing from the research – reviewing other’s reports helps you to think out the box.”

As section editor, Cassera is responsible for determining the content for the yearly parasitology issue. And she has lofty goals for the parasitology section. She is particularly interested in topics other journals are not covering and that expand the reader’s thoughts on the subject.

“I want readers to have more questions than answers after reading the review,” said Cassera. “I want the articles to spark new ideas.”

For her first issue, she came up with a list of topics and approached researchers that could write on the subjects. However, she is open to unsolicited submissions.

“I would like to include papers for different parasites, but what I’m really looking for are papers that bring new questions to the topic,” said Cassera. “If the scientific community would benefit – if it will lead to new questions or shift our thinking, then I’m interested in it.”

If you have an idea for a possible white paper or review that you think would be a good fit for the parasitology section of Current Clinical Microbiology Reports, then contact Cassera.

Also, be sure to check out the latest reviews, two of which come from former CTEGD members:

Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency

Donna Huber on March 17, 2021

Purpose: Variants in NUS1 are associated with a congenital disorder of glycosylation, developmental and epileptic encephalopathies, and are possible contributors to Parkinson disease pathogenesis. How the diverse functions of the NUS1-encoded Nogo B receptor (NgBR) relate to these different phenotypes is largely unknown. We present three patients with de novo heterozygous variants in NUS1 that cause a complex movement disorder, define pathogenic mechanisms in cells and zebrafish, and identify possible therapy.

Methods: Comprehensive functional studies were performed using patient fibroblasts, and a zebrafish model mimicking NUS1 haploinsufficiency.

Results: We show that de novo NUS1 variants reduce NgBR and Niemann-Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation. Reducing nus1 expression 50% in zebrafish embryos causes abnormal swim behaviors, cholesterol accumulation in the nervous system, and impaired turnover of lysosomal membrane proteins. Reduction of cholesterol buildup with 2-hydroxypropyl-ß-cyclodextrin significantly alleviates lysosomal proteolysis and motility defects.

Conclusion: Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.

Seok-Ho Yu, Tong Wang, Kali Wiggins, Raymond J. Louie, Emilio F. Merino, Cindy Skinner, Maria B. Cassera, Kirsten Meagher, Paul Goldberg, Neggy Rismanchi, Dillon Chen, Michael J. Lyons, Heather Flanagan-Steet & Richard Steet. Genet Med. 2021 Mar 17. doi: 10.1038/s41436-021-01137-6.

Resistance to some, but not other dimeric lindenane sesquiterpenoid esters is mediated by mutations in a Plasmodium falciparum esterase

Donna Huber on September 24, 2020

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P. falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50 = 1.6 nM, n=34) against fresh Ugandan P. falciparum isolates. Analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

Joshua H Butler, Rodrigo P Baptista, Ana Lisa Valenciano, Bin Zhou, Jessica C Kissinger, Patrick K Tumwebaze, Philip J Rosenthal, Roland Cooper, Jian-Min Yue, Maria Belen Cassera. ACS Infect Dis. 2020 Sep 24. doi: 10.1021/acsinfecdis.0c00487

Probing the B- & C-rings of the antimalarial tetrahydro-β-carboline MMV008138 for steric and conformational constraints

Donna Huber on September 5, 2020

The antimalarial candidate MMV008138 (1a) is of particular interest because its target enzyme (IspD) is absent in human. To achieve higher potency, and to probe for steric demand, a series of analogs of 1a were prepared that featured methyl-substitution of the B- and C-rings, as well as ring-chain transformations. X-ray crystallography, NMR spectroscopy and calculation were used to study the effects of these modifications on the conformation of the C-ring and orientation of the D-ring. Unfortunately, all the B- and C-ring analogs explored lost in vitro antimalarial activity. The possible role of steric effects and conformational changes on target engagement are discussed.

Sha Ding, Maryam Ghavami, Joshua H.Butler, Emilio F. Merino, Carla Slebodnick, Maria B. Cassera, Paul R. Carlier. Bioorg Med Chem Lett. 2020 Sep 5;127520. doi: 10.1016/j.bmcl.2020.127520

Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum

Donna Huber on August 6, 2020

The cis-polyisoprenoid lipids namely polyprenols, dolichols and their derivatives are linear polymers of several isoprene units. In eukaryotes, polyprenols and dolichols are synthesized as a mixture of four or more homologues of different length with one or two predominant species with sizes varying among organisms. Interestingly, co-occurrence of polyprenols and dolichols, i.e. detection of a dolichol along with significant levels of its precursor polyprenol, are unusual in eukaryotic cells. Our metabolomics studies revealed that cis-polyisoprenoids are more diverse in the malaria parasite Plasmodium falciparum than previously postulated as we uncovered active de novo biosynthesis and substantial levels of accumulation of polyprenols and dolichols of 15 to 19 isoprene units. A distinctive polyprenol and dolichol profile both within the intraerythrocytic asexual cycle and between asexual and gametocyte stages was observed suggesting that cis-polyisoprenoid biosynthesis changes throughout parasite’s development. Moreover, we confirmed the presence of an active cis-prenyltransferase (PfCPT) and that dolichol biosynthesis occurs via reduction of the polyprenol to dolichol by an active polyprenol reductase (PfPPRD) in the malaria parasite.

Flavia M Zimbres, Ana Lisa Valenciano, Emilio F Merino, Anat Florentin, Nicole R Holderman, Guijuan He, Katarzyna Gawarecka, Karolina Skorupinska-Tudek, Maria L Fernández-Murga, Ewa Swiezewska, Xiaofeng Wang, Vasant Muralidharan, Maria Belen Cassera. Sci Rep. 2020 Aug 6;10(1):13264. doi: 10.1038/s41598-020-70246-0.

Flavanones From the Twigs and Barks of Artocarpus Lakoocha Having Antiplasmodial and Anti-TB Activities

Donna Huber on July 1, 2020

Chromatographic separation of the acetone extracts from the twigs and barks of Artocarpus lakoocha led to the isolation of the one new flavanone, lakoochanone (1), together with eleven known compounds (2-12). Lakoochanone (1) and moracin C (4) exhibited weak antiplasmodial activity against Plasmodium falciparum Dd2 with IC50 values of 36.7 and 33.9 µM, respectively. Moreover, moracin C (4) and sanggenofuran B (5) showed cytotoxic activity against A2780 cell line with the respective IC50 values of 15.0 and 57.1 µM. In addition, cyclocommunin (7) displayed strong antimycobacterial activity against Mycobacterium tuberculosis H37Ra with the minimum inhibitory concentration (MIC) value of 12.3 µM.

Sirada Boonyaketgoson, Yongle Du, Ana L. Valenciano Murillo, Maria B. Cassera, David G. I. Kingston, Kongkiat Trisuwan. Chem Pharm Bull (Tokyo). 2020;68(7):671-674. doi: 10.1248/cpb.c20-00080.

Limonoids From Cipadessa baccifera

Donna Huber on May 29, 2020

Eighteen new limonoids, including eight methyl angolensates (1–8) and 10 cipadesins (9–18), were isolated from the leaves of Cipadessa baccifera. Their structures were characterized by means of spectroscopic data analyses, single-crystal X-ray diffraction, and quantum chemistry computational methods. The C-6 configurations in those compounds possessing a C-6 hydroxy group were all assigned as S regardless of the magnitude of J5,6, and the C-2′ configuration in those bearing a 2-methylbutyryl residue was defined by single-crystal X-ray diffraction and NMR data. Compounds 1, 5, 6, 7, 11, and 12 showed moderate antimalarial activities with IC50 values ranging from 12 to 28 μM.

Jin-Hai Yu, Hua Zhang, Bin Zhou, Flavia M. Zimbres, Seema Dalal, Qun-Fang Liu, Maria B. Cassera, and Jian-Min Yue. J Nat Prod. 2020 May 29. doi: 10.1021/acs.jnatprod.9b00666.

Antimalarial Diterpenoids From Vitex Rotundifolia: Isolation, Structure Elucidation, and in Vitro Antiplasmodial Activity

Donna Huber on May 12, 2020

Vitex rotundifolia is an important medicinal plant frequently employed in traditional medicines for the treatment of various ailments. Although this plant species has been under exploration for its constituents by various research groups including our own group, no reports were found regarding the antimalarial potential of this plant or of its purified phytochemicals. Phytochemical investigation of this plant yielded three new (1-3) and five known (4-8) diterpenoids. These compounds were purified by modern chromatographic techniques and their structures were determined by advanced spectroscopic techniques such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The in vitro antiplasmodial activities were encouraging, as compounds 2, 6, and 8 were found to have significant IC50 values of 1.2, 1.3 and 11.0 µM, respectively against Plasmodium falciparum.

You Ah Kim, Abdul Latif, Chang-Suk Kong, Youngwan Seo, Seema R Dalal, Maria B Cassera, David G I Kingston. Bioorg Chem. 2020 May 12;100:103925. doi: 10.1016/j.bioorg.2020.103925.

Galtonosides A-E: Antiproliferative and Antiplasmodial Cholestane Glycosides from Galtonia regalis

Donna Huber on March 31, 2020

An extract of Galtonia regalis from the Natural Products Discovery Institute showed moderate antiplasmodial activity, with an IC50 value less than 1.25 μg/mL. The two known cholestane glycosides 1 and 2 and the five new cholestane glycosides galtonosides A–E (3–7) were isolated after bioassay-directed fractionation. The structures of the new compounds were determined by interpretation of their NMR and mass spectra. Among these compounds, galtonoside B (4) displayed the most potent antiplasmodial activity, with an IC50 value of 0.214 μM against the drug-resistant Dd2 strain of Plasmodium falciparum.

Yongle Du, Brooke A. Martin, Ana Lisa Valenciano, Jason A. Clement, Michael Goetz, Maria B. Cassera, David G. I. Kingston. J Nat Prod. 2020 Mar 31. doi: 10.1021/acs.jnatprod.9b01064.

Anibamine and Its Analogues: Potent Antiplasmodial Agents from Aniba citrifolia

Donna Huber on October 2, 2019

In our continuing search for novel natural products with antiplasmodial activity, an extract of Aniba citrifolia was found to have good activity, with an IC50 value less than 1.25 μg/mL. After bioassay-directed fractionation, the known indolizinium alkaloid anibamine (1) and the new indolizinium alkaloid anibamine B (2) were isolated as the major bioactive constituents, with antiplasmodial IC50 values of 0.170 and 0.244 μM against the drug-resistant Dd2 strain of Plasmodium falciparum. The new coumarin anibomarin A (3), the new norneolignan anibignan A (5), and six known neolignans (7–12) were also obtained. The structures of all the isolated compounds were determined based on analyses of 1D and 2D NMR spectroscopic and mass spectrometric data, and the absolute configuration of anibignan A (5) was assigned from its ECD spectrum. Evaluation of a library of 28 anibamine analogues (13–40) indicated that quaternary charged analogues had IC50 values as low as 58 nM, while uncharged analogues were inactive or significantly less active. Assessment of the potential effects of anibamine and its analogues on the intraerythrocytic stages and morphological development of P. falciparum revealed substantial activity against ring stages for compounds with two C-10 side chains, while those with only one C-10 side chain exhibited substantial activity against trophozoite stages, suggesting different mechanisms of action.

Yongle Du, Ana Lisa Valenciano, Yumin Dai, Yi Zheng, Feng Zhang, Yan Zhang, Jason Clement, Michael Goetz, David G. I. Kingston, Maria B. Cassera. 2019. J Nat Prod. doi: 10.1021/acs.jnatprod.9b00724.