SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M
, is ...a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (
and
) targeting M
Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M
in complex with
or
, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of
and
are covalently bound to cysteine 145 of M
Both compounds showed good pharmacokinetic properties in vivo, and
also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
The literature on clientelism, the informal exchange of benefits for political support, has proliferated over the last three decades. However, the existing literature largely ignores the role of ...religion in shaping clientelism in contemporary politics. In particular, few attempts have been made to explore the relationship between religious ideology and clientelism at the party level: How does political parties’ religious ideology impact their clientelist linkages with citizens? This study uses cross-national data of parties in the Middle East and North Africa (MENA) from the V-Party database (1970–2019) to answer this question. Our findings reveal that religious parties are more clientelist than secular parties in the MENA. Particularly, parties’ ties with social organizations mediate the relationship between religious ideology and clientelism. This study extends the literature on the impact of religion on informal political institutions by focusing on the ideology and linkage strategy of political parties in the MENA.
Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on ...emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC
values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.
A catalytic system‐controlled divergent reaction strategy was here reported to construct four types of intriguing spiroheterocyclic skeletons from simple and readily available starting materials via ...a precise chemical bond activation/n+1 annulation cascade. The tetraazaspiroheterocyclic and trizazspiroheterocyclic scaffolds could be independently constructed by a selective N−N bond activation/n+1 annulation cascade, a C(sp2)‐H activation/4+1 annulation and a novel tandem C(sp2)‐H/C(sp3)−H bond activation/4+1 annulation strategy, along with a broad scope of substrates, moderate to excellent yields and valuable transformations. More importantly, in these transformations, we are the first time to capture a N−N bond activation and a C(sp3)−H bond activation of pyrazolidinones under different catalytic system.
Four types of novel and complicated spiropyrazolones from pyrazolidinones and diazopyrazolones were constructed via a precise chemical bond activation/n+1 annulation route, especially a selective N−N bond activation/n+1 annulation cascade and a novel tandem C(sp2)−H/C(sp3)−H bond activation/4+1 annulation strategy, and diazopyrazolones acted as unexpected 1C synthons.
Here, we report a novel strategy for constructing maleimide-containing peptides and cyclic peptides using Rh(III)-catalyzed tryptophan (Trp) (C7) alkenylation, which is challenging due to the ...inherent reactivity of the indole benzenoid ring. This method is scalable and exhibits broad substrate scope. The utility of this protocol could further be demonstrated by the synthesis of peptide conjugates with natural products and amino acids as well as the construction of maleimide-braced cyclic peptides.
A method to synthesize pyrazolo1,2‐acinnolines via rhodium(III)‐catalyzed C−H activation of pyrazolidinones and subsequent 4+2 annulation of sulfoxonium ylides was developed. 5‐Substituted or ...5,10‐disubstituted pyrazolo1,2‐acinnolines could be obtained by slightly adjusting the reaction conditions. Gram‐scale synthesis and practical transformations proved the practicability of this method. The mechanism of this method was proposed in the article on the basis of preliminary mechanistic results and previous reports. This method features simplified operation, metal‐oxidant free, and readily available reactants.
The transition‐metal‐catalyzed C−H activation and annulation reactions of pyrazolidinones with 4‐vinyl‐1,3‐dioxolan‐2‐one or vinylene carbonate are described herein. This protocol provided two types ...of pyrazolo1,2‐acinnolines as essential assets for the development of bioactive compounds, and the synthetic practicality was performed and explained with 44 examples. The possible mechanism of these two reactions is proposed based on preliminary studies and previous reports, and no oxidant was added to both reactions.
The construction of 2‐deoxy‐C‐glycosides has gradually become a hotspot of carbohydrate chemistry in recent years. In this work, we present an efficient, regioselective, stereoselective and widely ...applicable strategy for the synthesis of 2‐indolyl‐C‐deoxyglycosides via Ir(I)‐catalyzed, pyridine‐group‐directed C−H functionalization. This method exhibits high tolerance for the functional groups of indoles and the protecting groups of carbohydrates. Moreover, this protocol has good stereoselectivity and mainly produces β‐configuration products. Gram‐scale synthesis and several practical transformations were conducted for further applications. Meantime, we also explored the mechanism of this method and proposed a catalytic cycle
A method to synthesize pyrazolo1,2‐acinnolines via rhodium(III)‐catalyzed C−H activation of pyrazolidinones and subsequent 4+2 annulation of sulfoxonium ylides was developed. 5‐Substituted or ...5,10‐disubstituted pyrazolo1,2‐acinnolines could be obtained by slightly adjusting the reaction conditions. Gram‐scale synthesis and practical transformations proved the practicability of this method. The mechanism of this method was proposed in the article on the basis of preliminary mechanistic results and previous reports. This method features simplified operation, metal‐oxidant free, and readily available reactants.
Heterocycle-braced cyclic peptides have demonstrated enhanced metabolic stability, increased potency and selectivity. Here, we present a rapid synthesis method for constructing ...Trp(C7)-alkene(E)-crosslinked cyclic peptides with potent anti-proliferative activities against cancer cells, through C-H alkenylation and macrolactamization. This report addresses critical challenges associated with the installation and removal of the directing group N-Piv, configuration selectivity of the olefin, and intramolecular cyclization. Notably, this method exhibits mild reaction conditions, traceless removal of the directing group, and high configuration selectivity.
Special E-configuration Trp-alkene crosslinks can be constructed at various linear peptides utilizing air-stable Rh(III) catalyst. In addition, an efficient synthesis method for constructing Trp(C7)-alkene(E)-crosslinked cyclic peptides was developed, and this method demonstrates several advantages, including mild reaction conditions, traceless removal of the directing group, and specific configuration selectivity. Display omitted
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