72 research outputs found
Rapid and scalable synthesis of innovative unnatural α,β or γ-amino acids functionalized with tertiary amines on their side-chains.
We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,β or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.journal article2015 Jul 072015 06 01importe
Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels.
Acid-sensing ion channels (ASICs) are neuronal Na <sup>+</sup> -selective ion channels that open in response to extracellular acidification. They are involved in pain, fear, learning, and neurodegeneration after ischemic stroke. 2-Guanidine-4-methylquinazoline (GMQ) was recently discovered as the first nonproton activator of ASIC3. GMQ is of interest as a gating modifier and pore blocker of ASICs. It has however a low potency, and exerts opposite effects on ASIC1a and ASIC3. To further explore the molecular mechanisms of GMQ action, we have used the guanidinium moiety of GMQ as a scaffold and tested the effects of different GMQ derivatives on the ASIC pH dependence and maximal current. We report that GMQ derivatives containing quinazoline and quinoline induced, as GMQ, an alkaline shift of the pH dependence of activation in ASIC3 and an acidic shift in ASIC1a. Another group of 2-guanidinopyridines shifted the pH dependence of both ASIC1a and ASIC3 to more acidic values. Several compounds induced an alkaline shift of the pH dependence of ASIC1a/2a and ASIC2a/3 heteromers. Compared to GMQ, guanidinopyridines showed a 20-fold decrease in the IC <sub>50</sub> for ASIC1a and ASIC3 current inhibition at pH 5. Strikingly, 2-guanidino-quinolines and -pyridines showed a concentration-dependent biphasic effect that resulted at higher concentrations in ASIC1a and ASIC3 inhibition (IC <sub>50</sub> > 100 μM), while causing at lower concentration a potentiation of ASIC1a, but not ASIC3 currents (EC <sub>50</sub> ≈ 10 μM). In conclusion, we describe a new family of small molecules as ASIC ligands and identify an ASIC subtype-specific potentiation by a subgroup of these compounds
Constraints on (2060) Chiron's size, shape, and surrounding material from the November 2018 and September 2019 stellar occultations
After the discovery of rings around the largest known Centaur object, (10199)
Chariklo, we carried out observation campaigns of stellar occultations produced
by the second-largest known Centaur object, (2060) Chiron, to better
characterize its physical properties and presence of material on its
surroundings. We predicted and successfully observed two stellar occultations
by Chiron. These observations were used to constrain its size and shape by
fitting elliptical limbs with equivalent surface radii in agreement with
radiometric measurements. Constraints on the (2060) Chiron shape are reported
for the first time. Assuming an equivalent radius of R =
105 km, we obtained a semi-major axis of a = 126 22 km.
Considering Chiron's true rotational light curve amplitude and assuming it has
a Jacobi equilibrium shape, we were able to derive a 3D shape with a semi-axis
of a = 126 22 km, b = 109 19 km, and c = 68 13 km, implying
in a volume-equivalent radius of R = 98 17 km, implying a density
of 1119 4 kg m. We determined the physical properties of the 2011
secondary events around Chiron, which may then be directly compared with those
of Chariklo rings, as the same method was used. Data obtained from SAAO in 2018
do not show unambiguous evidence of the proposed rings, mainly due to the large
sampling time. Meanwhile, we discarded the possible presence of a permanent
ring similar to (10199) Chariklo's C1R in optical depth and extension. Using
the first multi-chord stellar occultation by (2060) Chiron and considering it
to have a Jacobi equilibrium shape, we derived its 3D shape. New observations
of a stellar occultation by (2060) Chiron are needed to further investigate the
material's properties around Chiron, such as the occultation predicted for
September 10, 2023
TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to the inhibition of P. falciparum growth in human blood
After invading red blood cells (RBCs), Plasmodium falciparum (Pf) can export its own proteins to the host membrane and activate endogenous channels that are present in the membrane of RBCs. This transport pathway involves the Voltage Dependent Anion Channel (VDAC). Moreover, ligands of the VDAC partner TranSlocator PrOtein (TSPO) were demonstrated to inhibit the growth of the parasite. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Zn-protoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS). TSPO and VDAC isoforms are differentially expressed on erythroid cells in late differentiation states. TSPO2 and VDAC are present in the membranes of mature RBCs in a unique protein complex that changes the affinity of TSPO ligands after Pf infection. TSPO ligands dose-dependently inhibited parasite growth, and this inhibition was correlated to ZnPPIX uptake and ROS accumulation in the infected RBCs. Our results demonstrate that TSPO ligands can induce Pf death by increasing the uptake of porphyrins through a TSPO2-VDAC complex, which leads to an accumulation of ROS
Short-term effects of unilateral lesion of the primary motor cortex (M1) on ipsilesional hand dexterity in adult macaque monkeys
Although the arrangement of the corticospinal projection in primates is consistent with a more prominent role of the ipsilateral motor cortex on proximal muscles, rather than on distal muscles involved in manual dexterity, the role played by the primary motor cortex on the control of manual dexterity for the ipsilateral hand remains a matter a debate, either in the normal function or after a lesion. We, therefore, tested the impact of permanent unilateral motor cortex lesion on the manual dexterity of the ipsilateral hand in 11 macaque monkeys, within a time window of 60 days post-lesion. For comparison, unilateral reversible pharmacological inactivation of the motor cortex was produced in an additional monkey. Manual dexterity was assessed quantitatively based on three motor parameters derived from two reach and grasp manual tasks. In contrast to the expected dramatic, complete deficit of manual dexterity of the contralesional hand that persists for several weeks, the impact on the manual dexterity of the ipsilesional hand was generally moderate (but statistically significant) and, when present, lasted less than 20 days. Out of the 11 monkeys, only 3 showed a deficit of the ipsilesional hand for 2 of the 3 motor parameters, and 4 animals had a deficit for only one motor parameter. Four monkeys did not show any deficit. The reversible inactivation experiment yielded results consistent with the permanent lesion data. In conclusion, the primary motor cortex exerts a modest role on ipsilateral manual dexterity, most likely in the form of indirect hand postural control
Novel synthesis of 3,4-dihydro-5-bromo[1,4]oxazin-2-one derivatives, new protease inhibitor scaffold
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