Development and characterization of a novel conjugated methamphetamine vaccine.

BACKGROUND: Methamphetamine (METH) addiction is a major public health concern globally with limited management options. The development of a METH vaccine through hapten design has received significant attention as a promising platform for the potential treatment of METH addiction and overdose, however there is yet to be a successful candidate in human trials. RESEARCH DESIGN AND METHODS: In this study, we developed a novel conjugated METH vaccine using oxidized mannan (a polymannose) as an immunogenic carrier. A METH hapten was synthesized by using amphetamine and conjugated to mannan with a (Lysine-Glycine-Lysine-Glycine-lysine-Glycine-Lysine-Glycine-Lysine-Glycine) (KG)5 peptide linker. RESULTS: The reaction between amphetamine and (KG)5, oxidation of mannan, and conjugation of amphetamine-(KG)5 with oxidized mannan were confirmed by color tests, Fourier-transform infrared spectroscopy, gas and liquid chromatography mass spectrometry, thin-layer chromatography, and ultraviolet spectrophotometer. Additionally, the ability of the vaccine to generate antibodies was confirmed in C57BL/6 mice. CONCLUSIONS: The successful development and characterization of the METH-mannan conjugate vaccine, provides a potential therapeutic intervention to curb METH substance use disorders. Each step of vaccine development was characterized to aid in future research on these vaccines, and the immunogenicity shown in the animal models supports future evaluation of the approach. Future studies of the conjugated METH vaccine should evaluate the efficacy in animal models of acute and chronic METH to pave the way for human studies.

Alkyne activation and polyhedral reorganization in benzothiazolate-capped osmium clusters on reaction with diethyl acetylenedicarboxylate (DEAD) and ethyl propiolate.

The reactivity of the face-capped benzothiazolate clusters HOs3(CO)9[µ3-C7H3(R)NS] (1a, R = H; 1b, R = 2-CH3) with alkynes has been investigated. 1a reacts with DEAD at 67 °C to furnish the isomeric alkenyl clusters Os3(CO)9(µ-C7H4NS)(µ3-EtO2CCCHCO2Et) (2a and 3a). X-ray crystallographic analyses of 2a and 3a have confirmed the stereoisomeric relationship of these products and the regiospecific polyhedral expansion that follows the formal transfer of the hydride to the coordinated alkyne ligand in HOs3(CO)9(µ-C7H4NS)(η2-DEAD). The significant structural differences between the two isomers, as revealed by the solid-state structures, derives from the regiospecific cleavage of one of the three Os-Os bonds in the intermediate alkenyl cluster Os3(CO)9(µ-C7H4NS)(η1-EtO2CCCHCO2Et), which follows hydride transfer to the coordinated alkyne ligand in the pi compound HOs3(CO)9(µ-C7H4NS)(η2-DEAD). Control experiments confirm the reversibility of the reaction leading to the formation of 2a and 3a. Whereas heating either isomer in refluxing THF or benzene affords a binary mixture containing 2a and 3a, thermolysis in refluxing toluene leads to the activation of the alkenyl ligand and formation of the new cluster Os3(CO)9(µ-C7H4NS)(µ3-EtO2CCCH2) (4). 4 was independently synthesized from 1a and ethyl propiolate at room temperature. The computed mechanisms that account for the formation of 2a and 3a are presented, along with the mechanism for the reaction of 1a with ethyl propiolate to give 4.