α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

QSPR modeling of bioconcentration factor of nonionic compounds using Gaussian processes and theoretical descriptors derived from electrostatic potentials on molecular surface.

In the present study, geometrical structures were constructed and optimized for 122 nonionic organic compounds at the quantum-mechanical HF/6-31G level of theory. The electrostatic potentials and subsequent structural descriptors derived from them were obtained. Gaussian process, and for comparison purpose, multiple linear regression (MLR) and support vector machine (SVM), were then employed to build the quantitative structure-bioconcentration factor relationships. Systematical validations including internal leave-one-out cross-validation, the validation for external test set, as well as a more rigorous Monte Carlo cross-validation were made to confirm the reliability of the constructed models. It has been found that the quantities derived from electrostatic potential, V(min) and ∑V(s,ind)(-), together with the molecular volume (V(mc)), dipole moment (µ) and the energy level of highest occupied molecular orbital (E(HOMO)) can be well used to express the quantitative structure-property relationship of this sample set. Both linear and nonlinear models can give satisfactory results, and the GP, which be capable of handing with linear and nonlinear-hybrid relationship through a mixed covariance function, appears to have better fitting and predictive abilities than other two statistical methods. The coefficient of determination r(pred)(2) and root mean square error of prediction (RMSEP) for the external test set are 0.953 and 0.337, respectively.

[Clinical observation on point-through-point therapy of scalp electroacupuncture for treatment of facial spasm].

OBJECTIVE: To search for the best method of increasing clinical therapeutic effect of facial spasm. METHODS: One hundred and twenty cases of facial spasm were selected and divided randomly into a scalp point-through-point electroacupuncture group (EA treatment group), an electroacupuncture control group (EA control group) and a carbamazepine control group, 40 cases in each group. Baihui (GV 20)-through-Qubin (GB 7), Shenting (GV 24)-through-Hanyan (GB 4), Touwei (ST 8)-through-Xuanli (GB 6), Benshen (GB 13)-through-Shuaigu (GB 8) were selected in the EA treatment group, and Baihui (GV 20), Yangbai (GB 14), Dicang (ST 4), Jiache (ST 6), Yifeng (TE 17), Hegu (LI 4), Taichong (LR 3) and Sanyinjiao (SP 6) were selected in the EA control group, and the EA treatment was given once each day, for 30 days. The carbamazepine control group were treated with carbamazepine 0.1 g, twice each day, for 30 days. Their therapeutic effects were evaluated by changes of grading of facial spasm strength and frequency, and myoelectric activity. RESULTS: The strength and frequency of facial spasm significantly decreased in the EA treatment group with very significant differences as compared with other two groups (P<0.01), and there was a significant difference in the electrophysiologic indexes as the EA treatment group compared with other two groups (P<0.05). CONCLUSION: Scalp point-through-point electroacupuncture can increase therapeutic effect on facial spasm and it is a better therapy for this disease.