The uniqueness of on-demand male contraception.

Because nearly half of pregnancies worldwide are unintended, available contraceptive methods are inadequate. Moreover, due to the striking imbalance between contraceptive options available for men compared to the myriad of options available to women, there is an urgent need for new methods of contraception for men. This review summarizes ongoing efforts to develop male contraceptives highlighting the unique aspects particular to on-demand male contraception, where a man takes a contraceptive only when and as often as needed.

Mouse sperm energy restriction and recovery (SER) revealed novel metabolic pathways.

Mammalian sperm must undergo capacitation to become fertilization-competent. While working on mice, we recently developed a new methodology for treating sperm which results in higher rates of fertilization and embryo development after fertilization. Sperm incubated in media devoid of nutrients lose motility, although they remain viable.

Capacitation induces changes in metabolic pathways supporting motility of epididymal and ejaculated sperm.

Mammalian sperm require sufficient energy to support motility and capacitation for successful fertilization. Previous studies cataloging the changes to metabolism in sperm explored ejaculated human sperm or dormant mouse sperm surgically extracted from the cauda epididymis. Due to the differences in methods of collection, it remains unclear whether any observed differences between mouse and human sperm represent species differences or reflect the distinct maturation states of the sperm under study.

Prey preference in a kleptoplastic dinoflagellate is linked to photosynthetic performance.

Dinoflagellates of the family Kryptoperidiniaceae, known as "dinotoms", possess diatom-derived endosymbionts and contain individuals at three successive evolutionary stages: a transiently maintained kleptoplastic stage; a stage containing multiple permanently maintained diatom endosymbionts; and a further permanent stage containing a single diatom endosymbiont. Kleptoplastic dinotoms were discovered only recently, in Durinskia capensis; until now it has not been investigated kleptoplastic behavior and the metabolic and genetic integration of host and prey. Here, we show D.

Architecture of androgen receptor pathways amplifying glucagon-like peptide-1 insulinotropic action in male pancreatic β cells.

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells.

characterization of sAC null sperm.

Targeted disruption of the soluble adenylyl cyclase (ADCY10; sAC) gene results in male-specific sterility without affecting spermatogenesis, mating behavior, or spermatozoa morphology and count; however, it dramatically impairs sperm motility and prevents capacitation. These phenotypes were identified in sperm from sAC null mice surgically extracted from the epididymis and studied . Epididymal sperm are dormant, and never exposed to physiological activators in semen or the female reproductive tract.

Carbonic Anhydrase Inhibitor Modulation of Intraocular Pressure Is Independent of Soluble Adenylyl Cyclase.

We investigated whether a clinically used carbonic anhydrase inhibitor (CAIs) can modulate intraocular pressure (IOP) through soluble adenylyl cyclase (sAC) signaling. IOP was measured 1 h after topical treatment with brinzolamide, a topically applied and clinically used CAIs, using direct cannulation of the anterior chamber in sAC knockout (KO) mice or C57BL/6J mice in the presence or absence of the sAC inhibitor (TDI-10229). Mice treated with the sAC inhibitor TDI-10229 had elevated IOP.

Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.

Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout.

Corrigendum: Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential.

[This corrects the article DOI: 10.3389/fphys.2022.

On-demand male contraception via acute inhibition of soluble adenylyl cyclase.

Nearly half of all pregnancies are unintended; thus, existing family planning options are inadequate. For men, the only choices are condoms and vasectomy, and most current efforts to develop new contraceptives for men impact sperm development, meaning that contraception requires months of continuous pretreatment. Here, we provide proof-of-concept for an innovative strategy for on-demand contraception, where a man would take a birth control pill shortly before sex, only as needed.

Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates.

Soluble adenylyl cyclase (sAC: ADCY10) is an enzyme involved in intracellular signaling. Inhibition of sAC has potential therapeutic utility in a number of areas. For example, sAC is integral to successful male fertility: sAC activation is required for sperm motility and ability to undergo the acrosome reaction, two processes central to oocyte fertilization.

Assessing potency and binding kinetics of soluble adenylyl cyclase (sAC) inhibitors to maximize therapeutic potential.

In mammalian cells, 10 different adenylyl cyclases produce the ubiquitous second messenger, cyclic adenosine monophosphate (cAMP). Amongst these cAMP-generating enzymes, bicarbonate (HCO )-regulated soluble adenylyl cyclase (sAC; ADCY10) is uniquely essential in sperm for reproduction. For this reason, sAC has been proposed as a potential therapeutic target for non-hormonal contraceptives for men.

Strategies to safely target widely expressed soluble adenylyl cyclase for contraception.

In humans, the prototypical second messenger cyclic AMP is produced by 10 adenylyl cyclase isoforms, which are divided into two classes. Nine isoforms are G protein coupled transmembrane adenylyl cyclases (tmACs; ADCY1-9) and the 10th is the bicarbonate regulated soluble adenylyl cyclase (sAC; ADCY10). This review details why sAC is uniquely druggable and outlines ways to target sAC for novel forms of male and female contraception.

Identification of sequence motifs in Lhcx proteins that confer qE-based photoprotection in the diatom Phaeodactylum tricornutum.

Photosynthetic organisms in nature often experience light fluctuations. While low light conditions limit the energy uptake by algae, light absorption exceeding the maximal rate of photosynthesis may go along with enhanced formation of potentially toxic reactive oxygen species. To preempt high light-induced photodamage, photosynthetic organisms evolved numerous photoprotective mechanisms.

Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10).

Soluble adenylyl cyclase (sAC) has gained attention as a potential therapeutic target given the role of this enzyme in intracellular signaling. We describe successful efforts to design improved sAC inhibitors amenable for interrogation of sAC inhibition to assess its potential therapeutic applications. This work culminated in the identification of TDI-10229 (), which displays nanomolar inhibition of sAC in both biochemical and cellular assays and exhibits mouse pharmacokinetic properties sufficient to warrant its use as an tool compound.

Bicarbonate, carbon dioxide and pH sensing via mammalian bicarbonate-regulated soluble adenylyl cyclase.

Soluble adenylyl cyclase (sAC; ADCY10) is a bicarbonate (HCO )-regulated enzyme responsible for the generation of cyclic adenosine monophosphate (cAMP). sAC is distributed throughout the cell and within organelles and, as such, plays a role in numerous cellular signalling pathways. Carbonic anhydrases (CAs) nearly instantaneously equilibrate HCO , protons and carbon dioxide (CO); because of the ubiquitous presence of CAs within cells, HCO -regulated sAC can respond to changes in any of these factors.

Soluble adenylyl cyclase regulates the cytosolic NADH/NAD redox state and the bioenergetic switch between glycolysis and oxidative phosphorylation.

The evolutionarily conserved soluble adenylyl cyclase (sAC, ADCY10) mediates cAMP signaling exclusively in intracellular compartments. Because sAC activity is sensitive to local concentrations of ATP, bicarbonate, and free Ca, sAC is potentially an important metabolic sensor. Nonetheless, little is known about how sAC regulates energy metabolism in intact cells.

Capacitation increases glucose consumption in murine sperm.

Mammalian sperm acquire fertilization capacity in the female reproductive tract in a process known as capacitation. During capacitation, sperm change their motility pattern (i.e.

Metabolic changes in mouse sperm during capacitation†.

Mammalian sperm are stored in the epididymis in a dormant state. Upon ejaculation, they must immediately start producing sufficient energy to maintain motility and support capacitation. While this increased energy demand during capacitation is well established, it remains unclear how mouse sperm modify their metabolism to meet this need.

Optimization of lead compounds into on-demand, nonhormonal contraceptives: leveraging a public-private drug discovery institute collaboration†.

Efforts to develop new male or female nonhormonal, orally available contraceptives assume that to be effective and safe, targets must be (1) essential for fertility; (2) amenable to targeting by small-molecule inhibitors; and (3) restricted to the germline. In this perspective, we question the third assumption and propose that despite its wide expression, soluble adenylyl cyclase (sAC: ADCY10), which is essential for male fertility, is a valid target. We hypothesize that an acute-acting sAC inhibitor may provide orally available, on-demand, nonhormonal contraception for men without adverse, mechanism-based effects.

Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis.

Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH.