Analysis
of the SARS-CoV-2 sequence revealed a multibasic furin
cleavage site at the S1/S2 boundary of the spike protein distinguishing
this virus from SARS-CoV. Furin, the best-characterized member of
the mammalian proprotein convertases, is an ubiquitously expressed
single pass type 1 transmembrane protein. Cleavage of SARS-CoV-2 spike
protein by furin promotes viral entry into lung cells. While furin
knockout is embryonically lethal, its knockout in differentiated somatic
cells is not, thus furin provides an exciting therapeutic target for
viral pathogens including SARS-CoV-2 and bacterial infections. Several
peptide-based and small-molecule inhibitors of furin have been recently
reported, and select cocrystal structures have been solved, paving
the way for further optimization and selection of clinical candidates.
This perspective highlights furin structure, substrates, recent inhibitors,
and crystal structures with emphasis on furin’s role in SARS-CoV-2
infection, where the current data strongly suggest its inhibition
as a promising therapeutic intervention for SARS-CoV-2.
Novel
beta-coronavirus SARS-CoV-2 is the pathogenic agent responsible for
coronavirus disease-2019 (COVID-19), a globally pandemic infectious
disease. Due to its high virulence and the absence of immunity among
the general population, SARS-CoV-2 has quickly spread to all countries.
This pandemic highlights the urgent unmet need to expand and focus
our research tools on what are considered “neglected infectious
diseases” and to prepare for future inevitable pandemics. This
global emergency has generated unprecedented momentum and scientific
efforts around the globe unifying scientists from academia, government
and the pharmaceutical industry to accelerate the discovery of vaccines
and treatments. Herein, we shed light on the virus structure and
life cycle and the potential therapeutic targets in SARS-CoV-2 and
briefly refer to both active and passive immunization modalities,
drug repurposing focused on speed to market, and novel agents against
specific viral targets as therapeutic interventions for COVID-19.
Tau aggregation is believed to have a strong association with the level of cognitive deficits in Alzheimer's disease (AD). Thus, optical brain imaging of tau aggregates has recently gained substantial attention as a promising tool for the early diagnosis of AD. However, selective imaging of tau aggregates is a major challenge due to sharing similar β−sheet structures with homologous Aβ fibrils. Herein, four quinoline-based fluorescent probes (Q-tau) were judiciously designed using the donor− acceptor architecture for selective imaging of tau aggregates. In particular, probe Q-tau 4 exhibited a strong intramolecular charge transfer and favorable photophysical profile, such as a large Stokes' shift and fluorescence emission wavelength of 630 nm in the presence of tau aggregates. The probe also displayed a "turn-on" fluorescence behavior toward tau fibrils with a 3.5-fold selectivity versus Aβ fibrils. In addition, Q-tau 4 exhibited nanomolar binding affinity to tau aggregates (K d = 16.6 nM), which was 1.4 times higher than that for Aβ fibrils. The mechanism of "turn-on" fluorescence was proposed to be an environment-sensitive molecular rotor-like response. Moreover, ex vivo labeling of human AD brain sections demonstrated favorable colocalization of Q-tau 4 and the phosphorylated tau antibody, while comparable limited staining was observed with Aβ fibrils. Molecular docking was conducted to obtain insights into the tau-binding mode of the probe. Collectively, Q-tau 4 has successfully been used as a tau-specific fluorescent imaging agent with lower background interference.
New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds 4b, 5e and 5f showed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds 4b, 5e and 5f revealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin.
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