3 research outputs found
Stereoselective Formation of Trisubstituted (<i>Z</i>)‑Chloroalkenes Adjacent to a Tertiary Carbon Stereogenic Center by Organocuprate-Mediated Reduction/Alkylation
A robust and efficient method for the synthesis of trisubstituted (<i>Z</i>)-chloroalkenes is described. A one-pot reaction of γ,γ-dichloro-α,β-enoyl sultams involving organocuprate-mediated reduction/asymmetric alkylation affords α-chiral (<i>Z</i>)-chloroalkene derivatives in moderate to high yields with excellent diastereoselectivity, and allylic alkylation of internal allylic <i>gem</i>-dichlorides is also demonstrated. This study provides the first examples of the use of allylic <i>gem</i>-dichlorides adjacent to the chiral center for novel 1,4-asymmetric induction
Study of an RNA-Focused DNA-Encoded Library Informs Design of a Degrader of a r(CUG) Repeat Expansion
A solid-phase DNA-encoded library (DEL) was studied for
binding
the RNA repeat expansion r(CUG)exp, the
causative agent of the most common form of adult-onset muscular dystrophy,
myotonic dystrophy type 1 (DM1). A variety of uncharged and novel
RNA binders were identified to selectively bind r(CUG)exp by using a two-color flow cytometry screen. The cellular
activity of one binder was augmented by attaching it with a module
that directly cleaves r(CUG)exp. In DM1
patient-derived muscle cells, the compound specifically bound r(CUG)exp and allele-specifically eliminated r(CUG)exp, improving disease-associated defects.
The approaches herein can be used to identify and optimize ligands
and bind RNA that can be further augmented for functionality including
degradation
Cell-Permeable Stapled Peptides Based on HIV‑1 Integrase Inhibitors Derived from HIV‑1 Gene Products
HIV-1
integrase (IN) is an enzyme which is indispensable for the stable
infection of host cells because it catalyzes the insertion of viral
DNA into the genome and thus is an attractive target for the development
of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory
activity against HIV-1 IN. These Vpr-derived peptides are originally
located in an α-helical region of the parent Vpr protein. Addition
of an octa-arginyl group to the inhibitory peptides caused significant
inhibition against HIV replication associated with an increase in
cell permeability but also relatively high cytotoxicity. In the current
study, stapled peptides, a new class of stabilized α-helical
peptidomimetics were adopted to enhance the cell permeability of the
above lead peptides. A series of stapled peptides, which have a hydrocarbon
link formed by a ruthenium-catalyzed ring-closing metathesis reaction
between successive turns of α-helix, were designed, synthesized,
and evaluated for biological activity. In cell-based assays some of
the stapled peptides showed potent anti-HIV activity comparable with
that of the original octa-arginine-containing peptide (<b>2</b>) but with lower cytotoxicity. Fluorescent imaging experiments revealed
that these stapled peptides are significantly cell permeable, and
CD analysis showed they form α-helical structures, whereas the
unstapled congeners form β-sheet structures. The application
of this stapling strategy to Vpr-derived IN inhibitory peptides led
to a remarkable increase in their potency in cells and a significant
reduction of their cytotoxicity