29 research outputs found
Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release
The
pharmacokinetic properties of tenofovir (TFV) and other charged
nucleoside analogues are dramatically improved upon conjugation to
a lipid prodrug. We previously prepared reduction-sensitive lipid
conjugates of TFV that demonstrate superior antiviral activity compared
to other lipid conjugates including the clinically approved formulation,
tenofovir disoproxil fumarate (TDF). In continuation of that work,
we have synthesized next-generation conjugates with reduced cytotoxicity
that retain potent antiviral activity against HIV-1 and HBV with a
therapeutic index >100000 for our most potent conjugate. We also
show
that disulfide reduction is not responsible for prodrug cleavage unless
3-<i>exo</i>-<i>tet</i> intramolecular cyclization
can occur, suggesting that enzymatic hydrolysis is predominantly responsible
for activity of our prodrugs in vitro
Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity
The therapeutic value of numerous
small molecules hinges on their
ability to permeate the plasma membrane. This is particularly true
for tenofovir (TFV), adefovir, and other antiviral nucleosides that
demonstrate potent antiviral activity but poor bioavailability. Using
TFV as a model substrate, we hybridized two disparate prodrug strategies
to afford novel reduction-sensitive lipid conjugates of TFV that exhibit
subnanomolar activity toward HIV-1 and are stable in human plasma
for more than 24 h with a therapeutic index approaching 30000. These
compounds significantly rival the clinically approved formulation
of TFV and revitalize the potential of disulfide-bearing prodrugs
which have seen limited in vitro and in vivo success since their debut
over 20 years ago. We further demonstrate the utility of these conjugates
as a tool to indirectly probe the enzymatic hydrolysis of phosphonomonoesters
that may further advance the development of other prodrug strategies
for nucleosides, peptides, and beyond
A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds
HIV resistance emerging against antiretroviral
drugs represents
a great threat to the continued prolongation of the lifespans of HIV-infected
patients. Therefore, methods capable of predicting resistance susceptibility
in the development of compounds are in great need. By targeting the
major reverse transcription residues Y181, K103, and L100, we used
the biological activities of compounds against these enzymes and the
wild-type reverse transcriptase to create NaiÌve Bayes Networks.
Through this machine learning approach, we could predict, with high
accuracy, whether a compound would be susceptible to a loss of potency
due to resistance. Also, we could perfectly predict retrospectively
whether compounds would be susceptible to both a K103 mutant RT and
a Y181 mutant RT. In the study presented here, our method outperformed
a traditional molecular mechanics approach. This method should be
of broad interest beyond drug discovery efforts, and serves to expand
the utility of machine learning for the prediction of physical, chemical,
or biological properties using the vast information available in the
literature
A Machine Learning Approach for Predicting HIV Reverse Transcriptase Mutation Susceptibility of Biologically Active Compounds
HIV resistance emerging against antiretroviral
drugs represents
a great threat to the continued prolongation of the lifespans of HIV-infected
patients. Therefore, methods capable of predicting resistance susceptibility
in the development of compounds are in great need. By targeting the
major reverse transcription residues Y181, K103, and L100, we used
the biological activities of compounds against these enzymes and the
wild-type reverse transcriptase to create NaiÌve Bayes Networks.
Through this machine learning approach, we could predict, with high
accuracy, whether a compound would be susceptible to a loss of potency
due to resistance. Also, we could perfectly predict retrospectively
whether compounds would be susceptible to both a K103 mutant RT and
a Y181 mutant RT. In the study presented here, our method outperformed
a traditional molecular mechanics approach. This method should be
of broad interest beyond drug discovery efforts, and serves to expand
the utility of machine learning for the prediction of physical, chemical,
or biological properties using the vast information available in the
literature
Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors
The HIV pandemic represents one of the most serious diseases
to
face mankind in both a social and economic context, with many developing
nations being the worst afflicted. Due to ongoing resistance issues
associated with the disease, the design and synthesis of anti-HIV
agents presents a constant challenge for medicinal chemists. Utilizing
molecular modeling, we have designed a series of novel cyclopropyl
indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors
and carried out their preparation. These compounds facilitate a double
hydrogen bonding interaction to Lys101 and efficiently occupy the
hydrophobic pockets in the regions of Tyr181/188 and Val179. Several
of these compounds inhibited HIV replication as effectively as nevirapine
when tested in a phenotypic assay
Examples of compounds of interest as sphingoid base/ceramide analog pharmaceutical leads
<p><b>Copyright information:</b></p><p>Taken from " Biodiversity of sphingoid bases (âsphingosinesâ) and related amino alcohols"</p><p></p><p>Journal of Lipid Research 2008;49(8):1621-1639.</p><p>Published online 1 Aug 2008</p><p>PMCID:PMC2444003.</p><p></p
StructureâActivity Relationships and Pharmacophore Model of a Noncompetitive Pyrazoline Containing Class of GluN2C/GluN2D Selective Antagonists
Here
we describe the synthesis and structureâactivity relationship
for a class of pyrazoline-containing dihydroquinolone negative allosteric
modulators of the NMDA receptor that show strong subunit selectivity
for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing
receptors. Several members of this class inhibit NMDA receptor responses
in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A
and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine,
nicotinic, serotonin, and purinergic receptors. Analysis of the purified
enantiomers of one of the more potent and selective compounds shows
that the <i>S</i>-enantiomer is both more potent and more
selective than the <i>R-</i>enantiomer. The <i>S</i>-enantiomer had an IC<sub>50</sub> of 0.17â0.22 ÎŒM at
GluN2D- and GluN2C-containing receptors, respectively, and showed
over 70-fold selectivity over other NMDA receptor subunits. The subunit
selectivity of this class of compounds should be useful in defining
the role of GluN2C- and GluN2D-containing receptors in specific brain
circuits in both physiological and pathophysiological conditions
The StructureâActivity Relationship of a Tetrahydroisoquinoline Class of <i>N</i>âMethylâdâAspartate Receptor Modulators that Potentiates GluN2B-Containing <i>N</i>âMethylâdâAspartate Receptors
We have identified a series of positive
allosteric NMDA receptor
(NMDAR) modulators derived from a known class of GluN2C/D-selective
tetrahydroisoquinoline analogues that includes CIQ. The prototypical
compound of this series contains a single isopropoxy moiety in place
of the two methoxy substituents present in CIQ. Modifications of this
isopropoxy-containing scaffold led to the identification of analogues
with enhanced activity at the GluN2B subunit. We identified molecules
that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C,
and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations
of agonist. Multiple compounds potentiate the response of NMDARs with
submicromolar EC<sub>50</sub> values. Analysis of enantiomeric pairs
revealed that the <i>S</i>-(â) enantiomer is active
at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the <i>R</i>-(+) enantiomer is only active at GluN2C/D subunits. These
results provide a starting point for the development of selective
positive allosteric modulators for GluN2B-containing receptors
Design, Synthesis, and StructureâActivity Relationship of a Novel Series of GluN2C-Selective Potentiators
NMDA
receptors are tetrameric complexes composed of GluN1 and GluN2AâD
subunits that mediate a slow Ca<sup>2+</sup><b>-</b>permeable
component of excitatory synaptic transmission. NMDA receptors have
been implicated in a wide range of neurological diseases and thus
represent an important therapeutic target. We herein describe a novel
series of pyrrolidinones that selectively potentiate only NMDA receptors
that contain the GluN2C subunit. The most active analogues tested
were over 100-fold selective for recombinant GluN2C-containing receptors
over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate
receptors. This series represents the first class of allosteric potentiators
that are selective for diheteromeric GluN2C-containing NMDA receptors
Pyrazolo-Piperidines Exhibit Dual Inhibition of CCR5/CXCR4 HIV Entry and Reverse Transcriptase
We
report novel anti-HIV-1 agents with combined dual hostâpathogen
pharmacology. Lead compound <b>3</b>, composed of a pyrazole-piperidine
core, exhibits three concurrent mechanisms of action: (1) non-nucleoside
reverse transcriptase inhibition, (2) CCR5-mediated M-tropic viral
entry inhibition, and (3) CXCR4-based T-tropic viral entry inhibition
that maintains native chemokine ligand binding. This discovery identifies
important tool compounds for studying viral infectivity and prototype
agents that block HIV-1 entry through dual chemokine receptor ligation