RESUMEN
A collection of ß-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds display promising bioactivity, providing a new potential therapeutic with a mode of action that differs versus any currently available clinical treatment.
Asunto(s)
Antimaláricos , Antimaláricos/farmacología , Plasmodium falciparum , Carbolinas/farmacología , Respuesta al Choque TérmicoRESUMEN
The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp90 inhibitors. Derivatization of XL888's scaffold led to the development of Tropane 1, as a PfHsp90-selective binder with nanomolar affinity. Hsp90 inhibitors exhibit anti-Plasmodium activity against the liver, asexual blood, and early gametocyte life stages. Thermal proteome profiling was implemented to assess PfHsp90-dependent proteome stability, and the proteasome-the main site of cellular protein recycling-was enriched among proteins with perturbed stability upon PfHsp90 inhibition. Subsequent biochemical and cellular studies suggest that PfHsp90 directly promotes proteasome hydrolysis by chaperoning the active 26S complex. These findings expand our knowledge of the PfHsp90-dependent proteome and protein quality control mechanisms in these pathogenic parasites, as well as further characterize this chaperone as a potential antimalarial drug target.
Asunto(s)
Antimaláricos , Plasmodium falciparum , Plasmodium falciparum/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteoma/metabolismo , Antimaláricos/química , Proteínas HSP90 de Choque Térmico , Chaperonas Moleculares/metabolismoRESUMEN
Intracellular protozoan parasites are responsible for wide-spread infectious diseases. These unicellular pathogens have complex, multi-host life cycles, which present challenges for investigating their basic biology and for discovering vulnerabilities that could be exploited for disease control. Throughout development, parasite proteomes are dynamic and support stage-specific functions, but detection of these proteins is often technically challenging and complicated by the abundance of host proteins. Thus, to elucidate key parasite processes and host-pathogen interactions, labeling strategies are required to track pathogen proteins during infection. Herein, we discuss the application of bioorthogonal non-canonical amino acid tagging and proximity-dependent labeling to broadly study protozoan parasites and include outlooks for future applications to study Plasmodium, the causative agent of malaria. We highlight the potential of these technologies to provide spatiotemporal labeling with selective parasite protein enrichment, which could enable previously unattainable insight into the biology of elusive developmental stages.
Asunto(s)
Malaria , Parásitos , Animales , Parásitos/metabolismo , Proteoma/metabolismo , Proteínas Protozoarias/metabolismo , Estadios del Ciclo de VidaRESUMEN
In this issue of Cell Chemical Biology, Vijayan and colleagues identify host factors integral for Plasmodium liver-stage infection using a whole-genome CRISPR-Cas9 knockout screen. Their efforts reveal that liver-stage parasites redistribute host microtubules to the parasite membrane in a process dependent on the host Golgi.
Asunto(s)
Malaria , Parásitos , Plasmodium , Animales , Sistemas CRISPR-Cas/genética , Hígado/metabolismo , Malaria/metabolismoRESUMEN
Plasmodium parasites extensively alter their host hepatocyte to evade host detection and support an unprecedented replication rate. Host cell manipulation includes association with the host early and late endomembrane systems, where Plasmodium accesses nutrients while suppressing cellular immune processes. Early endomembrane organelles provide an opportunity to sequester an abundance of lipids and proteins, but the association with late endomembrane organelles also risks autophagy-mediated elimination. While not all parasites survive, those that do benefit from a plethora of nutrients provided through this pathway. In this review, we discuss recent advances in our understanding of how Plasmodium parasites balance the need for host nutrients while avoiding elimination during the liver stage.
Asunto(s)
Parásitos , Plasmodium , Animales , Hepatocitos/parasitología , Hígado/parasitología , NutrientesRESUMEN
Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor active against blood stage Pf3D7 parasites. To establish structure-activity relationships for PfPK6 and PfGSK3, 52 analogues were synthesized and assessed for the inhibition of PfGSK3 and PfPK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual PfGSK3/PfPK6 inhibitors 23d (PfGSK3/PfPK6 IC50 = 172/11 nM) and 23e (PfGSK3/PfPK6 IC50 = 97/8 nM) with antiplasmodial activity (23d Pf3D7 EC50 = 552 ± 37 nM and 23e Pf3D7 EC50 = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual PfPK6/PfGSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.
Asunto(s)
Antimaláricos , Parásitos , Plasmodium , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Glucógeno Sintasa Quinasa 3 , Humanos , Plasmodium falciparum , Pirimidinas , Relación Estructura-ActividadRESUMEN
Cystic fibrosis (CF) is one of the most prevalent genetic diseases and a total of 1700 different genetic mutations can cause this condition. Patients that suffer this disease have a thickening of the mucus, creating an environment that promotes bacterial infections. Pseudomonas aeruginosa is a ubiquitous bacterium, which is frequently found in the lungs of CF patients. P. aeruginosa is known for its high level of antibiotic resistance as well as its high rate of mutation that allows it to rapidly evolve and adapt to a multitude of conditions. When a CF lung is infected with P. aeruginosa, the decay of the patient is accelerated, but there is little that can be done apart from controlling the infection with antibiotics. Novel strategies to control P. aeruginosa infection are imperative, and nanotechnology provides novel approaches to drug delivery that are more efficient than classic antibiotic treatments. These drug delivery systems are offering new prospects, especially for these patients with special mucus conditions and bacterial characteristics that limit antibiotic use.