Stereoelectronic Features of a Complex Ketene Dimerization Reaction

The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed.

Immunogenicity of clinically relevant SARS-CoV-2 vaccines in nonhuman primates and humans

Multiple preventive vaccines are being developed to counter the coronavirus disease 2019 pandemic. The leading candidates have now been evaluated in nonhuman primates (NHPs) and human phase 1 and/or phase 2 clinical trials. Several vaccines have already advanced into phase 3 efficacy trials, while others will do so before the end of 2020. Here, we summarize what is known of the antibody and T cell immunogenicity of these vaccines in NHPs and humans. To the extent possible, we compare how the vaccines have performed, taking into account the use of different assays to assess immunogenicity and inconsistencies in how the resulting data are presented. We also review the outcome of challenge experiments with severe acute respiratory syndrome coronavirus 2 in immunized macaques, while noting variations in the protocols used, including but not limited to the virus challenge doses. Press releases on the outcomes of vaccine efficacy trials are also summarized.

Involving Research Participants in a Pan-European Research Initiative: The EPAD Participant Panel Experience

Background Patient, public and participant involvement (PPPI) is increasingly acknowledged as a key pillar of successful research activity. PPPI can influence recruitment and retention, as well as researcher experience and contribute to decision making in research studies. However, there are few established methodologies of how to set up and manage PPPI activities. Methods In this paper we describe the set-up, running and experiences of the EPAD participant panel. The EPAD study was established as a pan-European cohort study aiming at understanding risks for developing Alzheimer’s disease and building a readiness cohort for Phase 2 clinical trials. Due to the longitudinal nature of this study, combined with the enrolment of healthy volunteers and those with mild cognitive impairments, the EPAD team highlighted PPPI involvement as crucial to the success of this project. The EPAD project employed a nested model, with local panels meeting at least twice a year established in England, France, Scotland, Spain and The Netherlands, feeding into a central panel who met once a year at the project’s General Assembly. The local panels were governed by terms of reference which were adaptable to meet local needs. We discuss the recruitment opportunities employed by the centres and the set-up of the panels. Results Impact of the panels has been widespread, and varies from feedback on documentation, to supporting with design of media materials and representation of the project at national and international meetings. Conclusions The EPAD panels have contributed to the success of the project and the model established is easily transferable to other disease areas investigating healthy or at-risk populations.

Alzheimer’s disease: An overview of the current treatments

Alzheimer’s disease (AD) affects millions of people around the world and although there are treatments that help control symptoms and slow down the progress of the disease, there is still no cure. Current treatments include three acetylcholine inhibitors, a glutamate inhibitor and a combination of the two. Due to the failure of hundreds of clinical trials with monotherapies, multitarget treatments are currently being investigated that consider both brain and peripheral factors. Gene therapy is one of the most promising therapies to treat and prevent the development of AD. Nowadays, there is no available medical treatment based on gene therapy to treat AD; however, there are treatments in phase 1 and phase 2 clinical trials with promising results. In this review, we will focus on the most important gene therapy treatments, CERE-110 (adeno-associated virus AAV2-Nerve Growth Factor), Intracerebral AAV gene delivery of APOE2 and gene therapy using PPARγ-coactivator-1α(PGC-1α)