27 research outputs found
CatSper as a Target for Male Contraception
Advisor: Gunda GeorgThis research was supported by the Undergraduate Research Opportunities Program (UROP)
Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception
Na,K-ATPase α4 is a testis-specific
plasma membrane Na<sup>+</sup> and K<sup>+</sup> transporter expressed
in sperm flagellum.
Deletion of Na,K-ATPase α4 in male mice results in complete
infertility, making it an attractive target for male contraception.
Na,K-ATPase α4 is characterized by a high affinity for the cardiac
glycoside ouabain. With the goal of discovering selective inhibitors
of the Na,K-ATPase α4 and of sperm function, ouabain derivatives
were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin
analogue <b>25</b>, carrying a benzyltriazole moiety at C17,
is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding
α4 isoform selectivity profile. Moreover, compound <b>25</b> decreased sperm motility in vitro and in vivo and affected sperm
membrane potential, intracellular Ca<sup>2+</sup>, pH, and hypermotility.
These results proved that the new ouabagenin triazole analogue is
an effective and selective inhibitor of Na,K-ATPase α4 and sperm
function
Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe
Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel fluorescence polarization pan-BET chemical probe suitable for high-throughput screening, structure–activity relationships, and hit-to-lead potency and selectivity assays to identify and characterize BET bromodomain inhibitors
Design, Synthesis, and in Vitro and in Vivo Evaluation of Ouabain Analogues as Potent and Selective Na,K-ATPase α4 Isoform Inhibitors for Male Contraception
Na,K-ATPase α4 is a testis-specific
plasma membrane Na<sup>+</sup> and K<sup>+</sup> transporter expressed
in sperm flagellum.
Deletion of Na,K-ATPase α4 in male mice results in complete
infertility, making it an attractive target for male contraception.
Na,K-ATPase α4 is characterized by a high affinity for the cardiac
glycoside ouabain. With the goal of discovering selective inhibitors
of the Na,K-ATPase α4 and of sperm function, ouabain derivatives
were modified at the glycone (C3) and the lactone (C17) domains. Ouabagenin
analogue <b>25</b>, carrying a benzyltriazole moiety at C17,
is a picomolar inhibitor of Na,K-ATPase α4, with an outstanding
α4 isoform selectivity profile. Moreover, compound <b>25</b> decreased sperm motility in vitro and in vivo and affected sperm
membrane potential, intracellular Ca<sup>2+</sup>, pH, and hypermotility.
These results proved that the new ouabagenin triazole analogue is
an effective and selective inhibitor of Na,K-ATPase α4 and sperm
function
The Fungal Sexual Pheromone Sirenin Activates the Human CatSper Channel Complex
The basal fungus <i>Allomyces
macrogynus</i> (<i>A. macrogynus</i>) produces motile
male gametes displaying well-studied
chemotaxis toward their female counterparts. This chemotaxis is driven
by sirenin, a sexual pheromone released by the female gametes. The
pheromone evokes a large calcium influx in the motile gametes, which
could proceed through the cation channel of sperm (CatSper) complex.
Herein, we report the total synthesis of sirenin in 10 steps and 8%
overall yield and show that the synthetic pheromone activates the
CatSper channel complex, indicated by a concentration-dependent increase
in intracellular calcium in human sperm. Sirenin activation of the
CatSper channel was confirmed using whole-cell patch clamp electrophysiology
with human sperm. Based on this proficient synthetic route and confirmed
activation of CatSper, analogues of sirenin can be designed as blockers
of the CatSper channel that could provide male contraceptive agents