Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection

On December 22,2021,the United States Food and Drug Administration approved the first main protease inhibitor,i.e.,oral antiviral nirmatrelvir(PF-07321332)/ritonavir(Paxlovid),for the treatment of early severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Nirmatrelvir inhibits SARSCoV-2 infection,but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression.The chiral structure of nirmatrelvir plays a key role in its antiviral activity.Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P4503A4 expression and occupying the plasma protein binding sites.Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir.However,Paxlovid has many contraindications.Some patients treated with Paxlovid experience a second round of coronavirus disease 2019(COVID-19)symptoms soon after recovery.Interestingly,the antiviral activity of nirmatrelvir metabolites,such as compounds 12e18,is similar to or higher than that of nirmatrelvir.Herein,we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.

有色ETFE薄膜光热性能试验研究

为满足建筑设计要求,有色ETFE薄膜被研制并应用于现代大型公共建筑。然而,作为一种新材料,有色ETFE薄膜的性能研究相对有限,特别是ETFE薄膜典型的光热性能特征。从实际工程应用出发,代表性地以成都农博园所采用的9种有色ETFE薄膜和1种无色透明ETFE薄膜为试验对象,对其透光性能和热工性能进行试验测试。首先使用紫外–可见–近红外分光光度计测量试验薄膜在太阳辐射波段内的透射率和反射率,通过对比有色ETFE薄膜与无色透明ETFE薄膜太阳辐射曲线的走势和波动,分析了有色ETFE薄膜与无色透明ETFE薄膜的透光性能和热辐射性能在太阳光波段内的变化,计算并获得了试验薄膜的可见光透过率和太阳辐射系数。采用激光散射法测试试验薄膜的热传导性能,计算得到室温条件下试验薄膜的导热系数和热阻。总结不同颜色ETFE薄膜的光热性能参数变化规律,并与无色透明ETFE薄膜进行比较,结果发现:1)在紫外光区,有色ETFE薄膜的透射率和反射率均处于较低水平(合计不超过30%),有色ETFE薄膜对紫外线的吸收能力强,实际使用中应注意有色ETFE薄膜的老化问题。2)有色ETFE薄膜的可见光透过率和太阳辐射透射系数均低于无色透明ETFE薄膜,导热系数略低于无色透明ETFE薄膜,太阳辐射吸收系数及相同厚度下的薄膜热阻均大于无色透明ETFE薄膜。3)影响有色ETFE薄膜可见光透过率、太阳辐射系数的主要因素是薄膜颜色的深浅,薄膜颜色越浅,其可见光透过率越大,太阳辐射透射系数越大,吸收系数越小;随着薄膜颜色加深,薄膜对太阳光的吸收能力逐渐增加,透射系数和反射系数相对处于较低水平。4)影响有色ETFE薄膜热阻的主要因素是薄膜厚度;相同厚度下,有色ETFE薄膜热阻高出无色透明ETFE薄膜7%~14%。研究结果表明,使用有色ETFE薄膜作为建筑围护结构,能增加围护结构对太阳辐射的反射和吸收作用,并在一定程度上阻挡热量传导,减少室内光照过度及夏季过热问题。

Nanozyme-activating prodrug therapies:A review

Enzyme prodrug therapies(EPTs)have been intensively explored as attractive approaches to selective activation of systemically administered benign prodrugs by the exogenous enzymes or enzymes expressed at the desired target site,thus achieving localized,site-specific therapeutic effect.Many effective strategies(e.g.,antibody-,viral-,gene-,as well as polymer-directed EPT)have been developed for enzyme localization to locally activate systemically administered benign prodrugs.Nevertheless,intrinsic limitations(e.g.,complex intracellular environment and catalyst instability)make the practical application of EPT strategies a task that presents itself as highly challenging.As a promising alternative to natural enzyme,nanozyme has attracted substantial attention since its discovery in 2007,mainly due to the advantages of robust catalytic activity,high stability,low cost,and facile synthesis.Recently,nanozyme-activated prodrug strategies bring a new opportunity for targeted therapy,referred to as nanozyme-activating prodrug therapies.This review focuses on recently reported nanozyme-activated prodrug strategies,aiming to provide some new insights into the potential applications in site-specific drug synthesis.

New insights into the suppression of inflammation and lipid accumulation by JAZF1

Atherosclerosis is one of the leading causes of disease and death worldwide.The identification of new therapeutic targets and agents is critical.JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue(AT).JAZF1 suppresses inflammation(including IL-1β,IL-4,IL-6,IL-8,IL-10,TNFα,IFN-γ,IAR-20,COL3A1,laminin,and MCP-1)by reducing NF-κB pathway activation and AT immune cell infiltration.JAZF1 reduces lipid accumulation by regulating the liver X receptor response element(LXRE)of the SREBP-1c promoter,the cAMP-response element(CRE)of HMGCR,and the TR4 axis.LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters,which suggests that JAZF1 regulates these genes through these sites.NF-κB is the center of the JAZF1-mediated inhibition of the inflammatory response.JAZF1 suppresses NF-κB expression by suppressing TAK1 expression.Interestingly,TAK1 inhibition also decreases lipid accumulation.A dual-targeting strategy of NF-κB and TAK1 could inhibit both inflammation and lipid accumulation.Dual-target compounds(including prodrugs)1–5 exhibit nanomolar inhibition by targeting NF-κB and TAK1,EGFR,or COX-2.However,the NF-κB suppressing activity of these compounds is relatively low(IC50>300 nM).Compounds 6–14 suppress NF-κB expression with IC50 values ranging from 1.8 nM to 38.6 nM.HS-276 is a highly selective,orally bioavailable TAK1 inhibitor.Combined structural modifications of compounds using a prodrug strategy may enhance NF-κB inhibition.This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumulation for the identification of new anti-atherosclerotic targets.

Selective N-terminal modification of peptides and proteins:Recent progresses and applications

Numerous strategies for linking desired chemical probes with target peptides and proteins have been developed and applied in the field of biological chemistry.Approaches for site-specific modification of native amino acid residues in test tubes and biological contexts represent novel biological tools for understanding the role of peptides and proteins.Selective N-terminal modification strategies have been broadly studied especially in the last 10 years,as N-terminal positions are typically solvent exposed and provide chemically distinct sites for many peptide and protein targets,making N terminus distinct from other functional groups.A growing number of chemical and enzymatic techniques have been developed to modify N-terminal amino acids,and those techniques have the potential in the fields of medicine,basic research and applied materials science.This review focuses on appraising modification methodologies with the potential for biological applications from the past 10 years.

Distance-directed Target Searching for a Deep Visual Servo SMA Driven Soft Robot Using Reinforcement Learning

Performing complex tasks by soft robots in constrained environment remains an enormous challenge owing to the limitations of flexible mechanisms and control methods.In this paper,a novel biomimetic soft robot driven by Shape Memory Alloy(SMA)with light weight and multi-motion abilities is introduced.We adapt deep learning to perceive irregular targets in an unstructured environment.Aiming at the target searching task,an intelligent visual servo control algorithm based on Q-leaming is proposed to generate distance-directed end effector locomotion.In particular,a threshold reward system for the target searching task is proposed to enable a certain degree of tolerance for pointing errors.In addition,the angular velocity and working space of the end effector with load and without load based on the established coupling kinematic model are presented.Our framework enables the trained soft robot to take actions and perform target searching.Realistic experiments under different conditions demonstrate the convergence of the learning process and effectiveness of the proposed algorithm.