CASTING: A Potent Supramolecular Strategy to Cytosolically Deliver STING Agonist for Cancer Immunotherapy and SARS-CoV-2 Vaccination

Stimulator of interferon genes,namely STING,an adaptor protein located in the endoplasmic reticulum,has been recognized as a shining target for cancer and infection research.However,STING agonists cyclic dinucleotides(CDNs)have shown almost zero efficacy in phase I clinical trials as a monotherapy,likely due to poor cellular permeability and rapid diffusion despite intratumoral injection.These deficiencies further affect other applications of CDNs,such as pandemic SARS-CoV-2 prevention and therapy.Here,we rationally design a supramolecular cytosolic delivery system based on controllable recognition of calixarene,namely CASTING(CAlixarene-STING),to improve CDN druggability,including degradation stability,cellular permeability,and tissue retention.CASTING efficiently enhances the immunostimulatory potency of CDGSF[a chemically modified cyclic di-GMP(CDG)]to generate an immunogenic microenvironment for melanoma regression,anti-PD-1 response rate increase,and durable memory formation against tumor recurrence.More importantly,CASTING displays a superior adjuvant activity on SARSCoV-2 recombinant spike/receptor binding domain vaccines,inducing robust and coordinated T-cell and antibody responses against SARS-CoV-2 infection in vivo.Collectively,the CASTING design represents an innovative advancement to facilitate the clinical translational capability of STING agonists.

Customized synthesis of phosphoprotein bearing phosphoserine or its nonhydrolyzable analog

Studies on the mechanism of protein phosphorylation and therapeutic interventions of its related molecular processes are limited by the difficulty in the production of purpose-built phosphoproteins harboring site-specific phosphorylated amino acids or their nonhydrolyzable analogs.Here we address this limitation by customizing the cell-free protein synthesis(CFPS)machinery via chassis strain selection and orthogonal translation system(OTS)reconfiguration screening.The suited chassis strains and reconfigured OTS combinations with high orthogonality were consequently picked out for individualized phosphoprotein synthesis.Specifically,we synthesized the sfGFP protein and MEK1 protein with site-specific phosphoserine(O-pSer)or its nonhydrolyzable analog,2-amino-4-phosphonobutyric acid(C-pSer).This study successfully realized building cell-free systems for site-specific incorporation of phosphonate mimics into the target protein.Our work lays the foundation for developing a highly expansible CFPS platform and the streamlined production of user-defined phosphoproteins,which can facilitate research on the physiological mechanism and potential interference tools toward protein phosphorylation.

New progress in active immunotherapy targeting to amyloid beta

Alzheimer's disease(AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins(Aβ), and it's suggested that Aβ may be the causative factor in AD pathogenesis. Immunotherapy targeting Aβ for preventing aggregation of Aβ and mildly clearing amyloid plaques has been a hot topic since 1999. Although the first clinical trial of Aβ vaccine, AN-1792, failed in phase II, its results suggested some key points in the design of Aβ vaccines. Avoiding the possible toxic Aβ specific T cell response and inducing a Th2 type cellular immune response may be beneficial for Aβ immunotherapy. Many associations and research groups are working on Aβ vaccine and some progress has been made in recent years. In this review, we have provided a detailed summary of past Aβ vaccines, which have been sorted by the immunogen, and we also discuss some recent progress and future perspectives.

Tau Protein Associated Inhibitors in Alzheimer Disease

Neurofibrillary tangles composed of tau protein and senile plaque accumulated by amyloid-β(Aβ)are two hallmarks in Alzheimer disease(AD).In the patients with AD,tau is abnormally hyperphosphorylated,mutated or misfolding,which endows tau with stronger tendency to aggregate.Tau protein has the potency to mediate neuron toxicity of Aβ.The reduction of tau level ameliorates degeneration of neuron axon.Therefore,many researches are exploring new methods to regulate tau level.This review will mainly focus on small molecules that can directly inhibit tau fibrillation or control tau accumulation by regulating tau phosphorylation process.