In this Opinion article, we aim to address how cells adapt to stress and the repercussions chronic stress has on cellular function. We consider acute and chronic stress-induced changes at the cellular level, with a focus on a regulator of cellular stress, the chaperome, which is a protein assembly that encompasses molecular chaperones, co-chaperones and other co-factors. We discuss how the chaperome takes on distinct functions under conditions of stress that are executed in ways that differ from the one-on-one cyclic, dynamic functions exhibited by distinct molecular chaperones. We argue that through the formation of multimeric stable chaperome complexes, a state of chaperome hyperconnectivity, or networking, is gained. The role of these chaperome networks is to act as multimolecular scaffolds, a particularly important function in cancer, where they increase the efficacy and functional diversity of several cellular processes. We predict that these concepts will change how we develop and implement drugs targeting the chaperome to treat cancer.
Highlights d N-glycosylation transforms a chaperone, GRP94, from a folder into a scaffolding protein d These changes are pathologic in nature as they remodel proteome-wide connectivity d The N-glycosylated GRP94 variant is a small and distinct fraction of the GRP94 pool d Proteome dysfunctions mediated by the N-glycosylated GRP94 variant are actionable
The fungal pathogen Candida albicans causes lethal systemic infections in humans. To better define how pathogens resist oxidative attack by the immune system, we examined a family of four Flavodoxin-Like Proteins (FLPs) in C. albicans. In agreement with previous studies showing that FLPs in bacteria and plants act as NAD(P)H quinone oxidoreductases, a C. albicans quadruple mutant lacking all four FLPs (pst1Δ, pst2Δ, pst3Δ, ycp4Δ) was more sensitive to benzoquinone. Interestingly, the quadruple mutant was also more sensitive to a variety of oxidants. Quinone reductase activity confers important antioxidant effects because resistance to oxidation was restored in the quadruple mutant by expressing either Escherichia coli wrbA or mammalian NQO1, two distinct types of quinone reductases. FLPs were detected at the plasma membrane in C. albicans, and the quadruple mutant was more sensitive to linolenic acid, a polyunsaturated fatty acid that can auto-oxidize and promote lipid peroxidation. These observations suggested that FLPs reduce ubiquinone (coenzyme Q), enabling it to serve as an antioxidant in the membrane. In support of this, a C. albicans coq3Δ mutant that fails to synthesize ubiquinone was also highly sensitive to oxidative stress. FLPs are critical for survival in the host, as the quadruple mutant was avirulent in a mouse model of systemic candidiasis under conditions where infection with wild type C. albicans was lethal. The quadruple mutant cells initially grew well in kidneys, the major site of C. albicans growth in mice, but then declined after the influx of neutrophils and by day 4 post-infection 33% of the mice cleared the infection. Thus, FLPs and ubiquinone are important new antioxidant mechanisms that are critical for fungal virulence. The potential of FLPs as novel targets for antifungal therapy is further underscored by their absence in mammalian cells.
Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer’s disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.
Keeping
in view various pharmacological attributes of indole and coumarin
derivatives, a new series of indolindione–coumarin molecular
hybrids was rationally designed and synthesized. All synthesized hybrid
molecules were evaluated for their antimicrobial potential against
Gram-negative bacterial strains (
Escherichia coli
and
Salmonella enterica
), Gram-positive
bacterial strains (
Staphylococcus aureus
and
Mycobacterium smegmatis
), and
four fungal strains (
Candida albicans
,
Alternaria mali
,
Penicillium
sp., and
Fusarium oxysporum
) by using the agar gel diffusion method. Among all synthetics, compounds
K-1
and
K-2
were found to be the best antimicrobial
agents with the minimum inhibitory concentration values of 30 and
312 μg/mL, against
Penicillium
sp. and
S. aureus
, respectively.
The biological data revealed some interesting facts about the structure–activity
relationship which state that the electronic environment on the indolinedione
moiety and carbon chain length between indolinedione and triazole
moieties considerably affect the antimicrobial potential of the synthesized
hybrids. Various types of binding interactions of
K-2
within the active site of
S. aureus
dihydrofolate reductase were also streamlined by molecular modeling
studies, which revealed the possible mechanism for potent antibacterial
activity of the compound.
Keeping in view various
pharmacological attributes of curcumin, coumarin, and isatin derivatives,
triazole-tethered monocarbonyl curcumin–coumarin and curcumin–isatin
molecular hybrids have been synthesized and evaluated for their antibacterial
potential against Gram-positive (
Enterococcus faecalis
and
Staphylococcus aureus
) and Gram-negative
(
Pseudomonas aeruginosa
and
Escherichia coli
) human pathogenic bacterial strains.
Among all hybrid molecules,
A-4
and
B-38
showed the most potent antibacterial activity with inhibition zones
of 29 and 31 mm along with MIC values of 12.50 and 6.25 μg/mL,
respectively. Structure–activity relationship that emerged
from biological data revealed that the two-carbon alkyl chain between
triazole and coumarin/isatin moiety is well tolerable for the activity.
Bromo substitution at the fifth position of isatin, para-cholo substitution
in the case of curcumin–isatin, and para-methoxy in the case
of curcumin–coumarin hybrids on ring A of curcumin are most
suitable groups for the antibacterial activity. Various types of binding
interactions of
A-4
and
B-38
within the
active site of dihydrofolate reductase (DHFR) of
S.
aureus
are also streamlined by molecular modeling
studies, suggesting their capability in completely blocking DHFR.
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