Vinylphosphonites react in chemoselective Staudinger-phosphonite reactions (SPhR) with azides to form vinylphosphonamidates for the subsequent modification of cysteine residues in peptides and proteins.
A good fit: Interactions between A‐kinase anchoring proteins (AKAPs) and protein kinase A (PKA) play key roles in a plethora of physiologically relevant processes whose dysregulation causes or is associated with diseases such as heart failure. Terpyridines have been developed as α‐helix mimetics for the inhibition of such interactions and are the first biologically active, nonpeptidic compounds that block the AKAP binding site of PKA.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Fluorine (
19
F) magnetic
resonance imaging (MRI) is severely
limited by a low signal-to noise ratio (SNR), and tapping it for
19
F drug detection in vivo still poses a significant challenge.
However, it bears the potential for label-free theranostic imaging.
Recently, we detected the fluorinated dihydroorotate dehydrogenase
(DHODH) inhibitor teriflunomide (TF) noninvasively in an animal model
of multiple sclerosis (MS) using
19
F MR spectroscopy (MRS).
In the present study, we probed distinct modifications to the CF
3
group of TF to improve its SNR. This revealed SF
5
as a superior alternative to the CF
3
group. The value
of the SF
5
bioisostere as a
19
F MRI reporter
group within a biological or pharmacological context is by far underexplored.
Here, we compared the biological and pharmacological activities of
different TF derivatives and their
19
F MR properties (chemical
shift and relaxation times). The
19
F MR SNR efficiency
of three MRI methods revealed that SF
5
-substituted TF has
the highest
19
F MR SNR efficiency in combination with an
ultrashort echo-time (UTE) MRI method. Chemical modifications did
not reduce pharmacological or biological activity as shown in the
in vitro dihydroorotate dehydrogenase enzyme and T cell proliferation
assays. Instead, SF
5
-substituted TF showed an improved
capacity to inhibit T cell proliferation, indicating better anti-inflammatory
activity and its suitability as a viable bioisostere in this context.
This study proposes SF
5
as a novel superior
19
F MR reporter group for the MS drug teriflunomide.
N‐Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. In search of effective inhibitors of MNK we applied high‐throughput screening of drug‐like small molecules. By applying different orthogonal assays for their validation we identified four potential MNK‐specific inhibitors with IC50 values in the low‐micromolar range. Molecular modelling of the inhibitors into the active site of MNK supports their binding to the sugar or the ATP‐binding pocket of the enzyme or both. These compounds are promising for downregulation of the sialic acid content of glycoconjugates and for studying the functional contribution of sialic acids to disease development.
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