ABSTRACT
The HIV-1 envelope glycoprotein (Env) trimer is the key target for vaccines aimed at inducing neutralizing antibodies (NAbs) against HIV-1. The clinical candidate immunogen ConM SOSIP.v7 is a stabilized native-like HIV-1 Env trimer based on an artificial consensus sequence of all HIV-1 isolates in group M. In preclinical studies ConM SOSIP.v7 trimers induced strong autologous NAb responses in non-human primates (NHPs). To fine-map these responses, we isolated monoclonal antibodies (mAbs) from six cynomolgus macaques that were immunized three times with ConM SOSIP.v7 protein and boosted twice with the closely related ConSOSL.UFO.664 immunogen. A total of 40 ConM and/or ConS-specific mAbs were isolated, of which 18 were retrieved after the three ConM SOSIP.v7 immunizations and 22 after the two immunizations with ConSOSL.UFO.664. 22 mAbs (55%) neutralized the ConM and/or ConS virus. Cross-neutralization of ConS virus by approximately one-third of the mAbs was seen prior to ConSOSL.UFO.664 immunization, albeit with modest potency. Neutralizing antibodies predominantly targeted the V1 and V2 regions of the immunogens, with an apparent extension towards the V3 region. Thus, the V1V2V3 region is immunodominant in the potent NAb response elicited by two consensus sequence native-like HIV-1 Env immunogens. Immunization with these soluble consensus Env proteins also elicited non-neutralizing mAbs targeting the trimer base. These results inform the use and improvement of consensus-based trimer immunogens in combinatorial vaccine strategies.
ABSTRACT
Adducts of TiCl4 with Lewis bases used as internal or external donors in heterogeneous Ziegler-Natta (ZN) catalysis represent a fundamental interaction contributing to the final composition of MgCl2 supported ZN-catalysts. This study presents the accurate experimental evaluation, from titration calorimetry, of the formation enthalpy of TiCl4 adducts with 15 Lewis bases of industrial interest. In addition, we report the accurate energies of association of TiCl4 with the same Lewis bases from calculations at the DLPNO-CCSD(T) level of theory. These accurate experimental and theoretical association values are compared with selected methods based on density functional theory (DFT) in combination with popular continuum solvation models. Calculations suggest that the PBE-D3, and M06 functionals in combination with a triple-ζ plus polarization quality basis set provide the best performance when the basis set superposition error (BSSE) is not removed from the association energies. Cleaning the association energies with the BSSE with the counterpoise protocol suggests B3LYP-D3, TPSS-D3 and M06L as the best performing functionals. The introduction of solvent effects with the PCM and SMD continuum solvation models allows the DFT-based association enthalpies to be compared with the experimental values obtained from titration calorimetry. Both solvation models in combination with the PBE-D3, PBE0-D3, B3LYP-D3, TPSS-D3, M06L, and M06 functionals provide association enthalpies close to the experimental values with MUEs in the range of 10-15 kJ mol-1.
ABSTRACT
The sulfonated tripodal polyaza-polycatechol-amine ligand tris(2,3-hydroxy-5-sulfobenzylamine) ethyl)amine (STRENCAT) was synthesized and its protonation constants determined by potentiometry at 25 degrees C and in 0.1 mol dm(-3) NaClO(4). In the adopted experimental conditions (2.5 < p[H(+)] < 11.5), six of the virtual thirteen protonation constants of STRENCAT were determined. The deprotonation sequence of STRENCAT, identified by UV-vis and NMR studies, is characterized by the initial loss of three catechol protons, between p[H(+)] 5 and 8, followed by the loss of three secondary ammonium protons at higher p[H(+)] (9 < p[H(+)] < 11.5). No deprotonation of the three, more basic, catechol sites of STRENCAT was observed even at the highest p[H(+)] studied. Complexation measurements run on lanthanide(iii)-STRENCAT systems (Ln = La, Gd and Yb), in the same ionic medium and temperature, show that the ligand (partly protonated or completely deprotonated) is able to form soluble 1 : 1 and 1 : 2 metal-ligand complexes over the whole p[H(+)] range investigated. Due to the high affinity of lanthanide(iii) for catecholate units, even at p[H(+)] near 10 and before ammonium deprotonation, STRENCAT forms tri-chelate complexes, in which the metal ions are hosted in the cage formed by the six catechol oxygen atoms, completely deprotonated. Deprotonation of secondary ammonium groups, although not directly involved in complexation, increases the stability of the 1 : 1 complexes. They prevail in solution at p[H(+)] > 10, even in excess of ligand, in all the metal-ligand systems.
ABSTRACT
The thermodynamic parameters of complexation of Ln(III) cations with tris(2-aminoethyl)amine (tren) and tetraethylenepentamine (tetren) were determined in dimethyl sulfoxide (DMSO) by potentiometry and calorimetry. The excitation and emission spectra and luminescence decay constants of Eu3+ and Tb3+ complexed by tren and tetren, as well as those of the same lanthanides(III) complexed with diethylenetriamine (dien) and triethylenetetramine (trien), were also obtained in the same solvent. The combination of thermodynamic and spectroscopic data showed that, in the 1:1 complexes, all nitrogens of the ligands are bound to the lanthanides except in the case of tren, in which the pendant N is bound. For the larger ligands (trien, tren, tetren) in the higher complexes (ML2), there was less complete binding by available donors, presumably due to steric crowding. FT-IR studies were carried out in an acetonitrile/DMSO mixture, suitably chosen to follow the changes in the primary solvation sphere of lanthanide(III) due to complexation of amine groups. Results show that the mean number of molecules of DMSO removed from the inner coordination sphere of lanthanides(III) is lower than ligand denticity and that the coordination number of the metal ions increases with amine complexation from approximately 8 to approximately 10. Independently of the number and structure of the amines, linear trends, similar for all lanthanides, were obtained by plotting the values of DeltaGj degrees, DeltaHj degrees, and TDeltaSj degrees for the complexation of ethylenediamine (en), dien, trien, tren, and tetren as a function of the number of amine metal-coordinated nitrogen atoms. The main factors on which the thermodynamic functions of lanthanide(III) complexation reactions in DMSO depend are discussed.
