4 research outputs found
Simplified Bryostatin Analogues Protect Cells from Chikungunya Virus-Induced Cell Death
Chikungunya virus (CHIKV) is a mosquito-borne
alphavirus showing a recent resurgence and rapid spread worldwide.
While vaccines are under development, there are currently no therapies
to treat this disease, except for over-the-counter (OTC) analgesics,
which alleviate the devastating arthritic and arthralgic symptoms.
To identify novel inhibitors of the virus, analogues of the natural
product bryostatin 1, a clinical lead for the treatment of cancer,
Alzheimer’s disease, and HIV eradication, were investigated
for <i>in vitro</i> antiviral activity and were found to
be among the most potent inhibitors of CHIKV replication reported
to date. Bryostatin-based therapeutic efforts and even recent anti-CHIKV
strategies have centered on modulation of protein kinase C (PKC).
Intriguingly, while the C ring of bryostatin primarily drives interactions
with PKC, A- and B-ring functionality in these analogues has a significant
effect on the observed cell-protective activity. Significantly, bryostatin
1 itself, a potent <i>pan</i>-PKC modulator, is inactive
in these assays. These new findings indicate that the observed anti-CHIKV
activity is not solely mediated by PKC modulation, suggesting possible
as yet unidentified targets for CHIKV therapeutic intervention. The
high potency and low toxicity of these bryologs make them promising
new leads for the development of a CHIKV treatment
Enhanced charge collection in MOF-525-PEDOT nanotube composites enable highly sensitive biosensing
[[abstract]]With the aim of a reliable biosensing exhibiting enhanced sensitivity and selectivity, this study demonstrates a dopamine (DA) sensor composed of conductive poly(3,4-ethylenedioxythiophene) nanotubes (PEDOT NTs) conformally coated with porphyrin-based metal-organic framework nanocrystals (MOF-525). The MOF-525 serves as an electrocatalytic surface, while the PEDOT NTs act as a charge collector to rapidly transport the electron from MOF nanocrystals. Bundles of these particles form a conductive interpenetrating network film that together: (i) improves charge transport pathways between the MOF-525 regions and (ii) increases the electrochemical active sites of the film. The electrocatalytic response is measured by cyclic voltammetry and differential pulse voltammetry techniques, where the linear concentration range of DA detection is estimated to be 2 × 10-6-270 × 10-6m and the detection limit is estimated to be 0.04 × 10-6m with high selectivity toward DA. Additionally, a real-time determination of DA released from living rat pheochromocytoma cells is realized. The combination of MOF5-25 and PEDOT NTs creates a new generation of porous electrodes for highly efficient electrochemical biosensing
Discovery of a Potent (4<i>R</i>,5<i>S</i>)‑4-Fluoro-5-methylproline Sulfonamide Transient Receptor Potential Ankyrin 1 Antagonist and Its Methylene Phosphate Prodrug Guided by Molecular Modeling
Transient receptor potential ankyrin
1 (TRPA1) is a non-selective
cation channel expressed in sensory neurons where it functions as
an irritant sensor for a plethora of electrophilic compounds and is
implicated in pain, itch, and respiratory disease. To study its function
in various disease contexts, we sought to identify novel, potent,
and selective small-molecule TRPA1 antagonists. Herein we describe
the evolution of an <i>N</i>-isopropylglycine sulfonamide
lead (<b>1</b>) to a novel and potent (4<i>R</i>,5<i>S</i>)-4-fluoro-5-methylproline sulfonamide series of inhibitors.
Molecular modeling was utilized to derive low-energy three-dimensional
conformations to guide ligand design. This effort led to compound <b>20</b>, which possessed a balanced combination of potency and
metabolic stability but poor solubility that ultimately limited <i>in vivo</i> exposure. To improve solubility and <i>in vivo</i> exposure, we developed methylene phosphate prodrug <b>22</b>, which demonstrated superior oral exposure and robust <i>in
vivo</i> target engagement in a rat model of AITC-induced pain
Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody–Drug Conjugates
A number
of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing
various disulfide-based prodrugs were evaluated for their ability
to undergo activation (disulfide cleavage) <i>in vitro</i> in the presence of either glutathione (GSH) or cysteine (Cys). A
good correlation was observed between <i>in vitro</i> GSH
stability and <i>in vitro</i> cytotoxicity toward tumor
cell lines. The prodrug-containing compounds were typically more potent
against cells with relatively high intracellular GSH levels (e.g.,
KPL-4 cells). Several antibody–drug conjugates (ADCs) were
subsequently constructed from PBD dimers that incorporated selected
disulfide-based prodrugs. Such HER2 conjugates exhibited potent antiproliferation
activity against KPL-4 cells <i>in vitro</i> in an antigen-dependent
manner. However, the disulfide prodrugs contained in the majority
of such entities were surprisingly unstable toward whole blood from
various species. One HER2-targeting conjugate that contained a thiophenol-derived
disulfide prodrug was an exception to this stability trend. It exhibited
potent activity in a KPL-4 <i>in vivo</i> efficacy model
that was approximately three-fold weaker than that displayed by the
corresponding parent ADC. The same prodrug-containing conjugate demonstrated
a three-fold improvement in mouse tolerability properties <i>in vivo</i> relative to the parent ADC, which did not contain
the prodrug