Jaeson Calla

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Judith L Green

University of California, Santa Barbara

E. Wayne Ross

University of British Columbia

David Seamon

Kansas State University

Armando Marques-Guedes

UNL - New University of Lisbon

Darren Obbard

University of Edinburgh

José F. González-Maya

Universidad Autónoma Metropolitana-Lerma

Diego F Cisneros-Heredia

Universidad San Francisco de Quito

Ulisses Caramaschi

Museu Nacional, UFRJ

Guilherme Moerbeck

UERJ - Universidade do Estado do Rio de Janeiro / Rio de Janeiro State University

Zlatozar Boev

National Museum of Natural History, Bulgarian Academy of Science

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Papers by Jaeson Calla

Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases

Journal of Medicinal Chemistry, Jan 11, 2024

PfMFR3: A Multidrug-Resistant Modulator in <i>Plasmodium falciparum</i>

ACS Infectious Diseases, Mar 15, 2021

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Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

bioRxiv (Cold Spring Harbor Laboratory), Nov 23, 2022

Changes in host cell morphology and transcription after apicomplexan parasite infection have long... more Changes in host cell morphology and transcription after apicomplexan parasite infection have long been noted, but there have been few studies of the functional consequences of host cell remodeling. Here we show, using time-dependent immunofluorescence microscopy of multiple human cell lines (HepG2, HC-04, Huh7.5.1 and primary human hepatocytes), infected with multiple Plasmodium species (Plasmodium berghei, P. falciparum and P. vivax (hypnozoites and schizonts)), and antibodies to multiple human proteins (HsNR4A3, HsMUC13, HsGOLGA8A, HsCGA, HsBiP, HsCXCL2), that human protein trafficking is extensively modified in Plasmodium infected cells. Using conventional as well as ultrastructure expansion microscopy we show that newly-synthesized human proteins are trafficked to the parasitophorous vacuole instead of the infected-cell plasma membrane, nucleus or extracellular space. Universal redirection of human signaling proteins cells the parasitophorous vacuole may provide a mechanistic explanation for how apicomplexan parasites can block host cells response to infection.

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Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

Chemistry: A European Journal, Mar 6, 2023

Supporting information for this article is given via a link at the end of the document/

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Antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro oral biofilm

F1000Research, Dec 23, 2021

Background: Natural products with antibacterial potential have begun to be tested on biofilm mode... more Background: Natural products with antibacterial potential have begun to be tested on biofilm models, bringing us closer to understanding the response generated by the complex microbial ecosystems of the oral cavity. The objective of this study was to evaluate the antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro biofilm of Streptococcus gordonii and Fusobacterium nucleatum. Methods: The experimental work involved a consecutive, in vitro, longitudinal, and double-blinded study design. Propolis samples were collected from 13 different regions of the Peruvian Andes. The disk diffusion method was used for the antimicrobial susceptibility test. The cytotoxic effect of propolis on human gingival fibroblasts was determined by cell viability method using the MTT (3-[4,5dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and the effect of propolis on the biofilm was evaluated by confocal microscopy and polymerase chain reaction (PCR). Results: The 0.78 mg/mL and 1.563 mg/mL concentrations of the methanolic fraction of the chloroform residue of Oxapampa propolis showed effects on biofilm thickness and the copy numbers of the srtA gene of S. gordonii and the radD gene of F. nucleatum at 48 and 120 hours, and chromatography (UV, λ 280 nm) identified rhamnocitrin, isorhamnetin, apigenin, kaempferol, diosmetin, acacetin, glycerol, and chrysoeriol.

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Human nuclear hormone receptor activity contributes to malaria parasite liver stage development

Cell Chemical Biology

The Non-Canonical Iron-Responsive Element of IRE-tvcp12 Hairpin Structure at the 3′-UTR of Trichomonas vaginalis TvCP12 mRNA That Binds TvHSP70 and TvACTN-3 Can Regulate mRNA Stability and Amount of Protein

Pathogens

Trichomonas vaginalis is one of the most common sexually transmitted parasites in humans. This pr... more Trichomonas vaginalis is one of the most common sexually transmitted parasites in humans. This protozoan has high iron requirements for growth, metabolism, and virulence. However, iron concentrations also differentially modulate T. vaginalis gene expression as in the genes encoding cysteine proteinases TvCP4 and TvCP12. Our goal was to identify the regulatory mechanism mediating the upregulation of tvcp12 under iron-restricted (IR) conditions. Here, we showed by RT-PCR, Western blot, and immunocytochemistry assays that IR conditions increase mRNA stability and amount of TvCP12. RNA electrophoretic mobility shift assay (REMSA), UV cross-linking, and competition assays demonstrated that a non-canonical iron-responsive element (IRE)-like structure at the 3′-untranslated region of the tvcp12 transcript (IRE-tvcp12) specifically binds to human iron regulatory proteins (IRPs) and to atypical RNA-binding cytoplasmic proteins from IR trichomonads, such as HSP70 and α-Actinin 3. These data w...

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Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

Chemistry – A European Journal

Here, we present remarkable epoxyketone‐based proteasome inhibitors with low nanomolar in vitro p... more Here, we present remarkable epoxyketone‐based proteasome inhibitors with low nanomolar in vitro potency for blood‐stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000‐fold greater selectivity for erythrocytic‐stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D‐amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171‐fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti‐malarial drugs.

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Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Changes in host cell morphology and transcription after apicomplexan parasite infection have long... more Changes in host cell morphology and transcription after apicomplexan parasite infection have long been noted, but there have been few studies of the functional consequences of host cell remodeling. Here we show, using time-dependent immunofluorescence microscopy of multiple human cell lines (HepG2, HC-04, Huh7.5.1 and primary human hepatocytes), infected with multiplePlasmodiumspecies (Plasmodium berghei, P. falciparumandP. vivax(hypnozoites and schizonts)), and antibodies to multiple human proteins (HsNR4A3, HsMUC13, HsGOLGA8A, HsCGA, HsBiP, HsCXCL2), that human protein trafficking is extensively modified inPlasmodiuminfected cells. Using conventional as well as ultrastructure expansion microscopy we show that newly-synthesized human proteins are trafficked to the parasitophorous vacuole instead of the infected-cell plasma membrane, nucleus or extracellular space. Universal redirection of human signaling proteins cells the parasitophorous vacuole may provide a mechanistic explanati...

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Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

ABSTRACTHere we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in ... more ABSTRACTHere we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,600-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 cells, which is largely driven by the accommodation of the parasite proteasome for a d-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.

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Identification of a Dual Liver-Asexual Stage Antimalarial Targeting Pfdhodh

American Journal of Tropical Medicine and Hygiene, 2018

Iron Responsive-like Elements in the parasite Entamoeba histolytica

Microbiology (Reading, England), Jan 18, 2017

In Entamoeba histolytica, iron modulates virulence and gene expression via unknown regulatory mec... more In Entamoeba histolytica, iron modulates virulence and gene expression via unknown regulatory mechanisms. The existence of a posttranscriptional iron regulatory system parallel to the IRE/IRP (Iron-Responsive Element/Iron Regulatory Protein) system in the protozoan Trichomonas vaginalis has recently been reported. Due to their evolutionary closeness and the importance of iron for growth and virulence in these protozoa, we hypothesized the existence of an IRE/IRP-like mechanism in E. histolytica. To determine the presence of IRE-like elements in some mRNAs from this parasite, we performed in silico analyses of the 5'- and 3'-UTRs of mRNAs encoding virulence factors and cytoskeleton, ribosomal, and metabolism proteins. The Zuker mfold software predicted IRE-like secondary structures in 52 of the 135 mRNAs analysed. However, only nine structures shared sequence similarity with the apical loop sequence (CAGUGN) of the previously reported human IRE-ferritin, whereas the GUU/UUG p...

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RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins

Biomolecules, 2015

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α-Actinin TvACTN3 ofTrichomonas vaginalisIs an RNA-Binding Protein That Could Participate in Its Posttranscriptional Iron Regulatory Mechanism

BioMed Research International, 2014

Trichomonas vaginalisis a sexually transmitted flagellated protist parasite responsible for trich... more Trichomonas vaginalisis a sexually transmitted flagellated protist parasite responsible for trichomoniasis. This parasite is dependent on high levels of iron, favoring its growth and multiplication. Iron also differentially regulates some trichomonad virulence properties by unknown mechanisms. However, there is evidence to support the existence of gene regulatory mechanisms at the transcriptional and posttranscriptional levels that are mediated by iron concentration inT. vaginalis. Thus, the goal of this study was to identify an RNA-binding protein inT. vaginalisthat interacts with the tvcp4 RNA stem-loop structure, which may participate in a posttranscriptional iron regulatory mechanism mediated by RNA-protein interactions. We performed RNA electrophoretic mobility shift assay (REMSA) and supershift, UV cross-linking, Northwestern blot, and western blot (WB) assays using cytoplasmic protein extracts fromT. vaginaliswith the tvcp4 RNA hairpin structure as a probe. We identified a 13...

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Aspectos moleculares de la resistencia a pirazinamida en M. tuberculosis: implicancias para el desarrollo de nuevos métodos de diagnóstico y terapéutica

Enfermedades del …, 2004

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A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum

PLOS Pathogens, 2022

Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium... more Potent and durable vaccine responses will be required for control of malaria caused by Plasmodium falciparum (Pf). RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the Pf circumsporozoite protein (PfCSP). Although most attention has focused on antibodies to repeat motifs on PfCSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously unde...

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α-Actinin TvACTN3 of Trichomonas vaginalis Is an RNA-Binding Protein That Could Participate in Its Posttranscriptional Iron Regulatory Mechanism

BioMed Research International, 2014

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Aspectos moleculares de la resistencia a pirazinamida en M. tuberculosis: implicancias para el desarrollo de nuevos métodos de diagnóstico y terapéutica

Enfermedades del …, 2004

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PfMFR3: A Multidrug-Resistant Modulator in Plasmodium falciparum

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Probing the Open Global Health Chemical Diversity Library for multistage-active starting points for next-generation antimalarials

ACS Infectious Diseases, Mar 4, 2020

Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-... more Most phenotypic screens aiming to discover new antimalarial chemotypes begin with low cost, high-throughput tests against the asexual blood stage (ABS) of the malaria parasite life cycle. Compounds active against the ABS are then sequentially tested in more difficult assays that predict whether a compound has other beneficial attributes. Although applying this strategy to new chemical libraries may yield new leads, repeated iterations may lead to diminishing returns and the rediscovery of chemotypes hitting well-known targets. Here, we adopted a different strategy to find starting points, testing ∼70,000 open source small molecules from the Global Health Chemical Diversity Library for activity against the liver stage, mature sexual stage, and asexual blood stage malaria parasites in parallel. In addition, instead of using an asexual assay that measures accumulated parasite DNA in the presence of compound (SYBR green), a real time luciferase-dependent parasite viability assay was used that distinguishes slow-acting (delayed death) from fast-acting compounds. Among 382 scaffolds with the activity confirmed by dose response (<10 μM), we discovered 68 novel delayed-death, 84 liver stage, and 68 stage V gametocyte inhibitors as well. Although 89% of the evaluated compounds had activity in only a single life cycle stage, we discovered six potent (half-maximal inhibitory concentration of <1 μM) multistage scaffolds, including a novel cytochrome bc1 chemotype. Our data further show the luciferase-based assays have higher sensitivity. Chemoinformatic analysis of positive and negative compounds identified scaffold families with a strong enrichment for activity against specific or multiple stages.

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Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases

Journal of Medicinal Chemistry, Jan 11, 2024

PfMFR3: A Multidrug-Resistant Modulator in <i>Plasmodium falciparum</i>

ACS Infectious Diseases, Mar 15, 2021

Download

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

bioRxiv (Cold Spring Harbor Laboratory), Nov 23, 2022

Download

Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

Chemistry: A European Journal, Mar 6, 2023

Supporting information for this article is given via a link at the end of the document/

Download

Antibacterial, antibiofilm, and cytotoxic activities and chemical compositions of Peruvian propolis in an in vitro oral biofilm

F1000Research, Dec 23, 2021

Download

Human nuclear hormone receptor activity contributes to malaria parasite liver stage development

Cell Chemical Biology

Pathogens

Download

Development of Potent and Highly Selective Epoxyketone‐Based Plasmodium Proteasome Inhibitors

Chemistry – A European Journal

Download

Plasmodium exoerythrocytic parasites redirect trafficking of human proteins to the parasitophorous vacuole

Changes in host cell morphology and transcription after apicomplexan parasite infection have long... more Changes in host cell morphology and transcription after apicomplexan parasite infection have long been noted, but there have been few studies of the functional consequences of host cell remodeling. Here we show, using time-dependent immunofluorescence microscopy of multiple human cell lines (HepG2, HC-04, Huh7.5.1 and primary human hepatocytes), infected with multiplePlasmodiumspecies (Plasmodium berghei, P. falciparumandP. vivax(hypnozoites and schizonts)), and antibodies to multiple human proteins (HsNR4A3, HsMUC13, HsGOLGA8A, HsCGA, HsBiP, HsCXCL2), that human protein trafficking is extensively modified inPlasmodiuminfected cells. Using conventional as well as ultrastructure expansion microscopy we show that newly-synthesized human proteins are trafficked to the parasitophorous vacuole instead of the infected-cell plasma membrane, nucleus or extracellular space. Universal redirection of human signaling proteins cells the parasitophorous vacuole may provide a mechanistic explanati...

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Development of Highly Selective Epoxyketone-based Plasmodium Proteasome Inhibitors with Negligible Cytotoxicity

Download

Identification of a Dual Liver-Asexual Stage Antimalarial Targeting Pfdhodh

American Journal of Tropical Medicine and Hygiene, 2018

Iron Responsive-like Elements in the parasite Entamoeba histolytica

Microbiology (Reading, England), Jan 18, 2017

Download

RNA-Binding Proteins in Trichomonas vaginalis: Atypical Multifunctional Proteins

Biomolecules, 2015

Download

α-Actinin TvACTN3 ofTrichomonas vaginalisIs an RNA-Binding Protein That Could Participate in Its Posttranscriptional Iron Regulatory Mechanism