Fine-tuning of macrophage activation using synthetic rocaglate derivatives

Bhattacharya, Bidisha; Chatterjee, Sujoy; Devine, William G.; Kobzik, Lester; Beeler, Aaron B.; Porco, John A.; Kramnik, Igor

doi:10.1038/srep24409

Cited by 16 publications

(24 citation statements)

References 65 publications

(76 reference statements)

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“…Our studies extend those of Bhattacharya et al (50) in documenting an antiinflammatory response by rocaglates. Importantly, we demonstrate that CR-1-31B, and related rocaglates, can be used to interdict this process in the brain, highlighting its potential use as an antimalarial drug for intervention in CM in humans.…”

Section: Discussionsupporting

confidence: 91%

Rocaglates as dual-targeting agents for experimental cerebral malaria

Langlais

Cencic

Moradin

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Cerebral malaria (CM) is a severe and rapidly progressing complication of infection by parasites that is associated with high rates of mortality and morbidity. Treatment options are currently few, and intervention with artemisinin (Art) has limited efficacy, a problem that is compounded by the emergence of resistance to Art in parasites. Rocaglates are a class of natural products derived from plants of the genus that have been shown to interfere with eukaryotic initiation factor 4A (eIF4A), ultimately blocking initiation of protein synthesis. Here, we show that the rocaglate CR-1-31B perturbs association of eIF4A (PfeIF4A) with RNA. CR-1-31B shows potent prophylactic and therapeutic antiplasmodial activity in vivo in mouse models of infection with (CM) and (blood-stage malaria), and can also block replication of different clinical isolates of in human erythrocytes infected ex vivo including drug-resistant isolates. In vivo, a single dosing of CR-1-31B in-infected animals is sufficient to provide protection against lethality. CR-1-31B is shown to dampen expression of the early proinflammatory response in myeloid cells in vitro and dampens the inflammatory response in vivo in -infected mice. The dual activity of CR-1-31B as an antiplasmodial and as an inhibitor of the inflammatory response in myeloid cells should prove extremely valuable for therapeutic intervention in human cases of CM.

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Section: Discussionsupporting

confidence: 91%

Rocaglates as dual-targeting agents for experimental cerebral malaria

Langlais

Cencic

Moradin

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Taken together these data demonstrate that macrophage activation by rocaglates is proportional to their translation inhibition activity. Importantly, general translational inhibitors, such as cycloheximide and puromycin, do not cause IRF1 co-stimulation, as described in our previous studies (15).…”

Section: Macrophage Activation By Rocaglates Is Coupled To Partial Trsupporting

confidence: 71%

“…Screening small molecule libraries, we found several synthetic rocaglates that potentiated pleiotropic effects of IFNγ on primary macrophages (15). Rocaglates are a class of bioactive derivatives of natural products isolated from medicinal plants of the Aglaia species that have been used in traditional Chinese medicine for treatment of fever, cough, diarrhea and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Channeling macrophage polarization via selective translation inhibition by rocaglates increases macrophage resistance to Mycobacterium tuberculosis

Chatterjee

Yabaji

Bhattacharya

et al. 2019

Preprint

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24The increasing problem of infectious diseases caused by antibiotic-resistant bacteria has 25 intensified a search for novel host-directed therapies aimed at either boosting immune-mediated 26 bacterial control or reducing immunopathology. Macrophages play central roles in eliminating 27 pathogens as well as in tissue homeostasis and repair via alternative activation programs, M1-28 like and M2-like, respectively. Macrophages of both phenotypes are often present at the sites of 29 chronic unresolved inflammation, such infectious granulomas and solid tumors, where the M2-30 like macrophages generate microenvironment conducive for pathogen survival or tumor 31 progression. 32Interferon-gamma is a major cytokine that drives M1-like macrophage activation, which 33 is essential for control of intracellular bacterial pathogens. To evaluate M1-like macrophage 34 polarization as a broad therapeutic strategy, we searched for small molecules capable of 35 enhancing effects of low concentrations of IFNγ on M1 macrophage polarization. We 36 identified synthetic rocaglates that potentiated macrophages responses to low concentrations 37 of IFNγ. Although known as potent translation inhibitors in tumor cell lines, in primary 38 macrophages select rocaglates induced the upregulation of IRF1, a master regulator of IFNγ 39-activated pathways, stimulated autophagy and increased macrophage resilience to oxidative 40 stress. In contrast, rocaglates inhibited macrophage responsiveness to IL-4, a prototypical 41 activator of the M2-like phenotype. The M1-like macrophage programing by rocaglates was 42 mechanistically linked to selective translation inhibition and modulation of MAP kinase 43 network. 44Thus, rocaglates represent a novel class of immunomodulators that can enforce 45 macrophage polarization towards the M1-like phenotype in complex microenvironments 46 3 associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g., 47chronic bacterial infections, allergies and, possibly, certain tumors. 48 49 50 51The increasing problem of infectious diseases caused by antibiotic-resistant bacteria has 52 intensified a search for novel therapeutic approaches. Among them are host-directed therapies 53 aimed at either boosting immune-mediated bacterial control or reducing immunopathology, 54 broadly referred to as mechanisms of host resistance or disease tolerance, respectively (1). 55Many intracellular bacterial pathogens reside in macrophages, the very cells of innate immune 56 system whose major function is to eliminate invading pathogens. This paradox is enabled by 57 macrophages' plasticity, which successful pathogens exploit to create cellular niches for 58 persistence and replication within inflamed tissue of susceptible hosts. 59To combat intracellular bacteria, macrophages activate cell autonomous defense 60 mechanisms, such as phagocytosis, production of highly toxic reactive oxygen and nitrogen 61 species, bactericidal peptides, as well as phagosome maturation and autophagy to deliver the 62 ingested pat...

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“…Methyl rocaglate ( 4 ) was found to be a specific inhibitor of TNFα-R or PMA-induced NF-κB activity in T cell lines [4,5][9-13] and rocaglamide was recently reported to inhibit cancer cell migration through Rho GTPase inhibition [14]. In a collaboration with Kramnik and co-workers, we found that the synthetic rocaglate derivatives ( 3 and 4 ) synergized with low concentrations of IFNγ in primary macrophages to stimulate expression of some IFN-inducible genes, including a key regulatory factor, Irf1, which activates autophagy [15]. …”

Section: Introductionmentioning

confidence: 99%