A5090293315- Malaria Research and Control
- Mosquito-borne diseases and control
- HIV Research and Treatment
- vaccines and immunoinformatics approaches
- Computational Drug Discovery Methods
- RNA and protein synthesis mechanisms
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Invertebrate Immune Response Mechanisms
- Evolution and Genetic Dynamics
- Trypanosoma species research and implications
- Calpain Protease Function and Regulation
- HIV/AIDS drug development and treatment
- RNA modifications and cancer
- Research on Leishmaniasis Studies
- Drug Transport and Resistance Mechanisms
- Ginger and Zingiberaceae research
- Parasites and Host Interactions
- Aquaculture disease management and microbiota
- Piperaceae Chemical and Biological Studies
- Vietnamese History and Culture Studies
- Neurobiology and Insect Physiology Research
- Vector-borne infectious diseases
- Pharmacogenetics and Drug Metabolism
- Quinazolinone synthesis and applications
Harvard University
2015-2025
Boston University
2021-2022
Broad Institute
2017-2018
University of California, San Diego
2012-2016
Scripps Research Institute
2009-2011
Swiss Tropical and Public Health Institute
2003-2008
Heidelberg University
1995
Universität Innsbruck
1995
German Cancer Research Center
1995
San Raffaele University of Rome
1995
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) identified chemical scaffolds potent forms. From this screen, we an imidazolopiperazine...
Transmission represents a population bottleneck in the Plasmodium life cycle and key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by...
Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome of 262
Malaria parasites elude eradication attempts both within the human host and across nations. At individual level, evade immune responses through antigenic variation. global escape drug pressure single nucleotide variants gene copy amplification events conferring resistance. Despite their importance to health, rates at which these genomic alterations emerge have not been determined. We studied complete genomes of different Plasmodium falciparum clones that had propagated asexually over one...
Drug resistance is an obstacle to global malaria control, as evidenced by the recent emergence and rapid spread of delayed artemisinin (ART) clearance mutant forms PfKelch13 protein in Southeast Asia. Identifying genetic determinants ART African-derived parasites important for surveillance understanding mechanism resistance. In this study, we carried out long-term vitro selection two recently isolated West African (from Pikine Thiès, Senegal) with increasing concentrations dihydroartemisinin...
Intraerythrocytic malaria parasites can obtain nearly their entire amino acid requirement by degrading host cell hemoglobin. The sole exception is isoleucine, which not present in adult human hemoglobin and must be obtained exogenously. We evaluated two compounds for potential to interfere with isoleucine utilization. Mupirocin, a clinically used antibacterial, kills Plasmodium falciparum at nanomolar concentrations. Thiaisoleucine, an analog, also has antimalarial activity. To identify...
Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates ring-stage survival under dihydroartemisinin vitro. Both phenotypes are mutations the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin emerging piperaquine Southeast Asia show that combination therapy, such as dihydroartemisinin–piperaquine, losing clinical effectiveness, prompting investigation drug mechanisms development strategies to surmount anti-malarial resistance....
An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS related bases elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, developed was applied to synthesis a series natural designed molecules, including epicoccin G (1), 8,8'-epi-ent-rostratin B (2), gliotoxin (3), (4), emethallicin E (5), haematocin (6). Biological screening selected synthesized...
Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread other endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence spread, develop effective strategies overcoming it. Here we analyze a mechanism PPQ Cambodian parasites. Isolates exhibit bimodal dose-response curve when exposed PPQ, with the area under quantifying their survival vitro. Increased copy number plasmepsin II...
The cytoplasmic prolyl-tRNA synthetase of Plasmodium falciparum is a dual-stage therapeutic target for drug development.
Identification of novel drug targets is a key component modern discovery. While antimalarial are often identified through the mechanism action studies on phenotypically derived inhibitors, this method tends to be time- and resource-consuming. The discoverable target space also constrained by existing compound libraries phenotypic assay conditions. Leveraging recent advances in protein structure prediction, we systematically assessed Plasmodium falciparum genome 867 candidate with evidence...
The identification of genetic changes that confer drug resistance or other phenotypic in pathogens can help optimize treatment strategies, support the development new therapeutic agents, and provide information about likely function genes. Elucidating mechanisms also assist identifying mode action uncharacterized but potent antimalarial compounds identified high-throughput chemical screening campaigns against Plasmodium falciparum.Here we show tiling microarrays detect de novo a large...
Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In evolution decoquinate-resistant parasites and subsequent comparative genomic analysis to drug-sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms gene encoding cytochrome b. The resultant amino acid mutations, A122T Y126C, reside within helix C ubiquinol-binding pocket b, an...
Summary Emerging resistance to first‐line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required protect existing drugs enhance efficacy. We report that piperazine‐containing compound ACT‐451840 exhibits single‐digit nanomolar inhibition of Plasmodium falciparum asexual blood stages transmissible gametocyte forms. Genome sequence analyses in vitro ‐derived ACT‐451840‐resistant parasites revealed single...
Abstract Identifying how small molecules act to kill malaria parasites can lead new “chemically validated” targets. By pressuring Plasmodium falciparum asexual blood stage with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. acyl-CoA synthetase (ACS) genes Pf ACS10 (PF3D7_0525100, M300I, A268D/V, F427L) ACS11 (PF3D7_1238800, F387V,...
Summary The Plasmodium falciparum virulence factor PfEMP1 is responsible for both antigenic variation and cytoadherence of infected erythrocytes in malaria. Approximately 50 var genes per parasite genome code this highly polymorphic surface protein. We showed recently that chromosome‐central subtelomeric are controlled by different promoters. Here, we report transcriptional repression located chromosomal regions occurs mechanisms. Subtelomeric gene transcription repressed 4–8 h before genes....
Here, we fully characterize the genomes of 14 Plasmodium falciparum patient isolates taken recently from Iquitos region using genome scanning, a microarray-based technique that delineates majority single-base changes, indels, and copy number variants distinguishing coding regions two clones. We show parasite population in Peruvian Amazon bears limited genotypes low recombination frequencies. Despite essentially clonal nature some isolates, see high frequencies mutations subtelomeric highly...
Whole-genome sequencing represents a powerful experimental tool for pathogen research. We present methods the analysis of small eukaryotic genomes, including streamlined system (called Platypus) finding single nucleotide and copy number variants as well recombination events. have validated our pipeline using four sets Plasmodium falciparum drug resistant data containing 26 clones from 3D7 Dd2 background strains, identifying an average 11 per clone. also identify 8 with contributions to...
The spread of insecticide resistance in Anopheles mosquitoes and drug Plasmodium parasites is contributing to a global resurgence malaria, making the generation control tools that can overcome these roadblocks an urgent public health priority. We recently showed transmission falciparum be efficiently blocked when exposing gambiae females antimalarials deposited on treated surface, with no negative consequences major components mosquito fitness. Here, we demonstrate this approach hurdles...
Malaria continues to impose a significant health burden in the continent of Africa with 213 million cases 2018 alone, representing 93% worldwide. Because high transmission malaria within continent, selection pressures develop drug resistance African parasites are distinct compared rest world. In light spread artemisinin conferred by C580Y mutation Pf Kelch13 propeller domain Southeast Asia, and its independent emergence South America, it is important study genetic determinants context using...
Plasma levels of the atherogenic lipoprotein[a] represent a quantitative genetic trait that is primarily controlled by polymorphic apolipoprotein[a] locus on chromosome 6q.The more than 1000-fold variation in plasma explained to large extent remarkable size polymorphism gene which translated into isoforms and unidentified sequence apo [a].In recent report, 1.5 kb fragment from 5' flanking region was associated with different promoter activities, led suggestion transcriptional control might...
The genetic background of a patient determines in part if person develops mild form malaria and recovers, or severe dies. We have used mouse model to detect genes involved the resistance susceptibility Plasmodium berghei infection. To this end we first characterized 32 different strains infected with P. identified survival as best trait discriminate between strains. found locus on chromosome 6 by linking phenotypes their variations using genome wide analyses such haplotype associated mapping...
Detecting de novo mutations in viral and bacterial pathogens enables researchers to reconstruct detailed networks of disease transmission is a key technique genomic epidemiology. However, these techniques have not yet been applied the malaria parasite, Plasmodium falciparum, which larger genome, slower generation times, complex life cycle make them difficult implement. Here, we demonstrate viability mutation studies P. falciparum for first time. Using combination sequencing, library...