Article
Chemistry, Medicinal
Barbara Forte, Sabine Ottilie, Andrew Plater, Brice Campo, Koen J. Dechering, Francisco Javier Gamo, Daniel E. Goldberg, Eva S. Istvan, Marcus Lee, Amanda K. Lukens, Case W. McNamara, Jacquin C. Niles, John Okombo, Charisse Flerida A. Pasaje, Miles G. Siegel, Dyann Wirth, Susan Wyllie, David A. Fidock, Beatriz Baragana, Elizabeth A. Winzeler, Ian H. Gilbert
Summary: This paper discusses the important criteria for selecting drug targets in antimalarial drug discovery, as well as the analysis of several drug targets in the MaIDA pipeline. Prioritizing targets ready to enter the drug discovery process can increase the likelihood of progressible drug candidates.
ACS INFECTIOUS DISEASES
(2021)
Article
Biochemistry & Molecular Biology
Wagner A. S. Judice, Leticia Silva Ferraz, Rayssa de Mello Lopes, Luan dos Santos Vianna, Fabio da Silva Siqueira, Juliana F. Di Iorio, Laura de Azevedo Maffeis Dalzoto, Mariana Nascimento Romero Trujilho, Taiz dos Reis Santos, Mauricio F. M. Machado, Tiago Rodrigues
Summary: Leishmaniasis and trypanosomiasis are endemic neglected diseases in South America and Africa, posing a significant public health problem. Current therapeutic options have limitations, leading to the search for new targets and treatments. Cysteine proteases are being investigated as promising targets for drug discovery against protozoal neglected diseases.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Review
Immunology
Gabriel W. Rangel, Manuel Llinas
Summary: Parasites of the phylum Apicomplexa impact humans worldwide, causing diseases such as toxoplasmosis, cryptosporidiosis, babesiosis, and malaria. Drug resistant pathogens are a major threat to current frontline chemotherapies, especially for widely used antimalarial drugs.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Microbiology
Ana Isabel Olias-Molero, Concepcion de la Fuente, Montserrat Cuquerella, Juan J. Torrado, Jose M. Alunda
Summary: Leishmaniasis, caused by Leishmania species, affects humans and animals with no available vaccine and relies mainly on chemotherapy. The currently used drugs are old, toxic, and expensive, with limited efficacy, facing challenges of growing resistance and therapeutic failure. The drug pipeline deconstruction impacts the high failure rate of potential drugs in the fight against this parasitic disease.
Article
Chemistry, Physical
Phuong Thuy Viet Nguyen, Giang Le Tra Nguyen, Oanh Thi Dinh, Cuong Quoc Duong, Lam H. Nguyen, Thanh N. Truong
Summary: Selecting suitable drug targets is crucial in drug discovery. This study used a combination of druggability filtering, molecular docking, and molecular dynamics simulations to select suitable targets for dengue and malaria. The study identified druggable targets and performed molecular docking and MD simulations to evaluate their binding affinities. The results identified specific targets for further drug design studies.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Microbiology
Fernanda de Moura Alves, Jessica Correa Bezerra Bellei, Camila de Souza Barbosa, Caique Lopes Duarte, Amanda Luisa da Fonseca, Ana Claudia de Souza Pinto, Felipe Oliveira Raimundo, Barbara Albuquerque Carpinter, Ari Sergio de Oliveira Lemos, Elaine Soares Coimbra, Alex Gutterres Taranto, Vinicius Novaes Rocha, Fernando de Pilla Varotti, Gustavo Henrique Ribeiro Viana, Kezia K. G. Scopel
Summary: In this study, a virtual screening of chemical entities against Plasmodium falciparum molecular targets led to the discovery of a potential antimalarial compound. Compound 10 showed the best results against cerebral malaria, with significant parasite growth inhibition and improved survival in the experimental model. Furthermore, compound 10 reduced the synthesis of NO, indicating its potential in preventing cerebral malaria.
Review
Microbiology
Dandugudumula Ramu, Shailja Singh
Summary: Leishmaniasis, the second-largest parasitic disease, lacks a licensed vaccine and treatment mainly relies on chemotherapy, facing issues such as inefficiency and drug resistance. Identifying novel molecular drug candidates is crucial in developing robust antileishmanials, with structure-based drugs targeting Leishmania enzymes/molecules offering a potential solution and insight into Leishmania biology.
FUTURE MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Malgorzata Kardynska, Jaroslaw Smieja, Pawel Paszek, Krzysztof Puszynski
Summary: Mathematical modeling is crucial for experimental research on signaling pathways and regulatory networks. However, existing sensitivity analysis methods may not be suitable for biological systems. This paper introduces a novel sensitivity analysis method that is particularly designed for identifying potential molecular drug targets in signaling pathways, and demonstrates its biological relevance with two sample models.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Pharmacology & Pharmacy
Geoffrey A. Holdgate, Catherine Bardelle, Alice Lanne, Jon Read, Daniel H. O'Donovan, James M. Smith, Nidhal Selmi, Robert Sheppard
Summary: This review provides an overview of the role of epigenetics in disease and the strategy of pharmacological intervention. It discusses the drug targets of epigenetics and the methods used for initial hit identification and chemical optimization. The review also highlights current challenges and future potential for epigenetics-based therapies.
DRUG DISCOVERY TODAY
(2022)
Review
Biochemistry & Molecular Biology
Orlando Elso, Guadalupe Garcia Linares, Valeria Sulsen
Summary: Infections caused by parasites are a global health issue and pose significant challenges. Current chemotherapy methods for these infections are often ineffective and associated with severe side effects. Drug resistance and varying susceptibility among different strains further complicate the situation. This review focuses on the potential of 1,4-dihydropyridines derivatives as a class of compounds for new drug development, discussing their antiparasitic activities and the development of new derivatives or repurposing of existing drugs for designing effective treatments.
CURRENT MEDICINAL CHEMISTRY
(2023)
Review
Microbiology
Francisco Guerra, Elizabeth Winzeler
Summary: Phenotypic screening methods have been instrumental in identifying potential antimalarial drug candidates, but recent efforts are focused on target-based drug discovery.
CURRENT OPINION IN MICROBIOLOGY
(2022)
Article
Immunology
Li Wang, Michael A. Crackower, Hao Wu
Summary: Inflammasome proteins are important drug targets for many diseases, but their drug discovery has been difficult due to challenges in solving high-resolution structures. Recent advances in the structural biology of NLRP3 and NLRP1 offer hope for structure-based drug design.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Crhisllane Rafaele dos Santos Vasconcelos, Antonio Mauro Rezende
Summary: Leishmaniasis, a neglected infectious disease, was studied using computational methods to evaluate potential drug targets in the predicted proteomes of Leishmania braziliensis and Leishmania infantum, revealing several untested proteins with potential therapeutic value.
FRONTIERS IN CHEMISTRY
(2021)
Review
Chemistry, Medicinal
Fernando Altamura, Rishi Rajesh, Carolina M. C. Catta-Preta, Nilmar S. Moretti, Igor Cestari
Summary: Human trypanosomiasis and leishmaniasis, caused by protozoan parasites, have become globally distributed tropical diseases due to human migration, climate change, and anthropogenic disturbance. The current chemotherapy for these diseases has limited efficacy and drug resistance is a growing concern. This review discusses the limitations of available drugs and highlights promising leads from current drug-based clinical trials. It also examines the challenges in target-based drug discovery and the advantages and limitations of modern research tools.
DRUG DEVELOPMENT RESEARCH
(2022)
Article
Microbiology
Adam J. Roberts, Han B. Ong, Simon Clare, Cordelia Brandt, Katherine Harcourt, Susanne U. Franssen, James A. Cotton, Nicole Mueller-Sienerth, Gavin J. Wright
Summary: This study aims to discover essential proteins for in vitro growth and host infection of Leishmania spp., with the goal of identifying subunit vaccine candidates. Through in silico analysis and genome editing, potential subunit vaccine candidates have been identified. Preclinical trials in a murine model showed significant levels of protection against splenic infection.
Article
Microbiology
Christopher A. Rice, Luis Fernando Lares-Jimenez, Fernando Lares-Villa, Dennis E. Kyle
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Parasitology
Eliza Vanessa Carneiro Alves-Ferreira, Tiago Rodrigues Ferreira, Pegine Walrad, Paul M. Kaye, Angela Kaysel Cruz
PARASITES & VECTORS
(2020)
Article
Biochemistry & Molecular Biology
Tiago R. Ferreira, Adam A. Dowle, Ewan Parry, Eliza V. C. Alves-Ferreira, Karen Hogg, Foteini Kolokousi, Tony R. Larson, Michael J. Plevin, Angela K. Cruz, Pegine B. Walrad
NUCLEIC ACIDS RESEARCH
(2020)
Article
Microbiology
Emma Troth, Dennis E. Kyle
Summary: The study validated alternative methods for assessing cell proliferation in Naegleria fowleri and developed a new drug screening assay. EdU incorporation was shown to be a complementary method for drug discovery for these neglected pathogens.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Chemistry, Medicinal
Andrii Monastyrskyi, Fabian Brockmeyer, Alexis N. LaCrue, Yingzhao Zhao, Steven P. Maher, Jordany R. Maignan, Vivian Padin-Irizarry, Yana Sakhno, Prakash T. Parvatkar, Ami H. Asakawa, Lili Huang, Debora Casandra, Sherwin Mashkouri, Dennis E. Kyle, Roman Manetsch
Summary: The prodrug approach of converting lead compounds into amino AOCOM ether-substituted analogues improves aqueous solubility and oral bioavailability, meeting key requirements typical for drug candidate profiles. The prodrug is activated through a pH-triggered intramolecular cyclization-elimination reaction, independent of biotransformations and animal-assisted processes. This novel approach was successfully demonstrated on antimalarial compounds, achieving single-dose cures in a rodent malaria model without advanced formulation techniques.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Logan Tillery, Kayleigh Barrett, Jenna Goldstein, Jared W. Lassner, Bram Osterhout, Nathan L. Tran, Lily Xu, Ryan M. Young, Justin Craig, Ian Chun, David M. Dranow, Jan Abendroth, Silvia L. Delker, Douglas R. Davies, Stephen J. Mayclin, Brandy Calhoun, Madison J. Bolejack, Bart Staker, Sandhya Subramanian, Isabelle Phan, Donald D. Lorimer, Peter J. Myler, Thomas E. Edwards, Dennis E. Kyle, Christopher A. Rice, James C. Morris, James W. Leahy, Roman Manetsch, Lynn K. Barrett, Craig L. Smith, Wesley C. Van Voorhis
Summary: Naegleria fowleri is a pathogenic amoeba that causes primary amebic meningoencephalitis by traveling to the brain via the olfactory nerves, thriving in warm freshwater environments with low drug sensitivity. Efforts have been made to identify potential drug targets through protein production and crystallography, with promising results of pathogen-specific inhibitors.
Article
Chemistry, Medicinal
Cynthia L. Lichorowic, Yingzhao Zhao, Steven P. Maher, Vivian Padin-Irizarry, Victoria C. Mendiola, Sagan T. de Castro, Jacob A. Worden, Debora Casandra, Dennis E. Kyle, Roman Manetsch
Summary: Research focuses on the antimalarial activity of artemisinin dimers, particularly the increase in activity of artemisinin moieties and the impact of deactivation caused by degradation of the peroxide bridge.
ACS INFECTIOUS DISEASES
(2021)
Article
Immunology
Kayla Sylvester, Steven P. Maher, Dora Posfai, Michael K. Tran, McKenna C. Crawford, Amelie Vantaux, Benoit Witkowski, Dennis E. Kyle, Emily R. Derbyshire
Summary: This study utilizes high-resolution microscopy to characterize temporal changes of the TVN in Plasmodium vivax liver stage, revealing its presence in dormant hypnozoites and association with host nuclei. The unexpected association of the host water channel protein AQP3 with TVN-derived vesicles is demonstrated, suggesting a potential function of AQP3 during this stage. These findings enhance understanding of host-parasite interactions in both dormant and replicating P. vivax liver stage forms.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2021)
Article
Public, Environmental & Occupational Health
Rebecca Barney, Miguel Velasco, Caitlin A. Cooper, Andrew Rashid, Dennis E. Kyle, Robert W. Moon, Gonzalo J. Domingo, Ihn Kyung Jang
Summary: This study assessed the cross-reactivity of different Plasmodium species with a specific antibody array for pLDH and found that P. ovale and P. malariae can be distinguished from P. falciparum based on the concentration ratio of PanLDH/PfLDH.
AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE
(2022)
Article
Multidisciplinary Sciences
Steven P. Maher, Amelie Vantaux, Victor Chaumeau, Adeline C. Y. Chua, Caitlin A. Cooper, Chiara Andolina, Julie Peneau, Melanie Rouillier, Zaira Rizopoulos, Sivchheng Phal, Eakpor Piv, Chantrea Vong, Sreyvouch Phen, Chansophea Chhin, Baura Tat, Sivkeng Ouk, Bros Doeurk, Saorin Kim, Sangrawee Suriyakan, Praphan Kittiphanakun, Nana Akua Awuku, Amy J. Conway, Rays H. Y. Jiang, Bruce Russell, Pablo Bifani, Brice Campo, Francois Nosten, Benoit Witkowski, Dennis E. Kyle
Summary: Improved control of Plasmodium vivax malaria can be achieved by discovering new antimalarials with radical cure efficacy, particularly targeting relapse caused by hypnozoites, to facilitate more targeted drug development.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Medicinal
Lucas Lorenzon, Jose C. Quilles Jr, Gustavo Daniel Campagnaro, Lissur Azevedo Orsine, Leticia Almeida, Flavio Veras, Rubens Daniel Miserani Magalhaes, Juliana Alcoforado Diniz, Tiago Rodrigues Ferreira, Angela Kaysel Cruz
Summary: In trypanosomatids, RNA-binding proteins (RBPs) play a crucial role in gene expression regulation through the posttranscriptional modification by protein arginine methyltransferases (PRMTs). This study functionally characterized the predicted PRMTs in Leishmania braziliensis and revealed the variation of R-methylation profiles among Leishmania species and different lifecycle stages. The results suggest the existence of a PRMT-interacting protein network and the importance of arginine methylation in parasite-host cell interactions.
ACS INFECTIOUS DISEASES
(2022)
Article
Microbiology
Carson Bowers, Lisa Hancox, Kristen Peissig, Justine C. C. Shiau, Amelie Vantaux, Benoit Witkowski, Sivchheng Phal, Steven P. P. Maher, John T. T. Harty, Dennis E. E. Kyle, Samarchith P. P. Kurup
Summary: This study presents a method for cryopreservation of malaria sporozoites, which successfully preserves their structural integrity, viability, and infectiousness, as well as transgenic properties. The research offers a reliable protocol for the long-term storage and recovery of human and murine malaria sporozoites and lays the groundwork for the widespread use of live sporozoites for research and clinical applications.
Article
Microbiology
A. Cassiopeia Russell, Dennis E. Kyle
Summary: The study investigated the drug susceptibility and growth rates of 11 different clinical isolates of the amoeba Naegleria fowleri, which causes a deadly brain infection. Significant differences in drug susceptibility and growth rates were found among the isolates, highlighting the need for additional clinical isolates in drug assays and the development of more targeted therapeutics. The findings provide a baseline for drug susceptibility among clinical isolates and suggest the potential for future combination therapy and research on mechanisms of action.
MICROBIOLOGY SPECTRUM
(2022)
Review
Parasitology
Daniella C. Bartholomeu, Santuza Maria Ribeiro Teixeira, Angela Kaysel Cruz
Summary: The availability of Trypanosomatid genomic data in public databases has led to numerous experimental possibilities, contributing to a more comprehensive understanding of the biology of these parasites and their interactions with hosts.
MEMORIAS DO INSTITUTO OSWALDO CRUZ
(2021)
Article
Biochemical Research Methods
Steven P. Maher, Amy J. Conway, Alison Roth, Swamy R. Adapa, Phillip Cualing, Chiara Andolina, James Hsiao, Jessica Turgeon, Victor Chaumeau, Myles Johnson, Chris Palmiotti, Naresh Singh, Samantha J. Barnes, Raahil Patel, Virginia Van Grod, Robert Carter, H. -C. Steve Sun, Jetsumon Sattabongkot, Brice Campo, Francois Nosten, Wajeeh M. Saadi, John H. Adams, Rays H. Y. Jiang, Dennis E. Kyle
