Hydrogen-bonded organic frameworks (HOFs) are porous materials with great potential for biological applications.T he self-assembly of HOFs and biomacromolecules, however,i sc hallenging.W er eport herein the self-assembly of nanoscale HOFs (nHOFs) to encapsulate protein for intracellular biocatalysis.T he self-assembly of tetrakis(4-amidiniumphenyl)methane and azobenzenedicarboxylate can encapsulate protein in situ to form protein@nHOFs under mild conditions.This strategy is applicable to proteins with different surface charge and molecular weight, showing ah igh protein encapsulation efficiency and minimal effect on protein activity. Acellular delivery study shows that the protein@TA-HOFs can efficiently enter cells and retain enzyme activity for biochemical catalysis in living cells for neuroprotection. Our strategy paves new avenues for interfacing nHOFs with biological settings and sheds light on expanding nHOFs as aplatform for biomacromolecule delivery and disease treatment.
f Enterovirus 71 (EV71) (Picornaviridae family) and hepatitis C virus (HCV) (Flaviviridae family) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2A pro ) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2A pro is the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2A pro , confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections. E nterovirus 71 (EV71) is one of the major etiological agents of human hand, foot, and mouth disease (HFMD) in the AsiaPacific region. Particularly, young children and immunodeficient populations are more susceptible to EV71 infection. EV71 infection results in severe aseptic meningitis, encephalitis, myocarditis, acute flaccid paralysis, and pulmonary edema, which lead to high fatality rates (1, 2). Chronic infection with hepatitis C virus (HCV) affects 180 million people worldwide, and 350,000 people die each year due to HCV-related complications (3). Hepatitis C not only affects the liver function but also induces liver fibrosis and cirrhosis, eventually leading to liver cancer (4).Both EV71 and HCV are positive-sense single-stranded RNA (ϩssRNA) viruses. EV71 is a member of the Enterovirus genus within the Picornaviridae family (5-7). The genome of EV71 encodes a polyprotein that is cleaved through viral proteases to generate four structural proteins (VP1 to VP4) required for viral capsid formation and seven nonstructural proteins (2A pro , 2B, 2C, 3A, 3B, 3C pro , and 3D pol ) for viral replication (8-10). HCV is a member of the Hepacivirus genus in the Flaviviridae family. The translated polyprotein of HCV is further processed into the structural proteins, including core protein and envelope glycoproteins E1 and E2; the nonstructural proteins are processed into NS2, NS3, NS4A, NS4B, NS5A, and NS5B (11).The successful replication of most viruses depends on the correct proteolytic processing of polyproteins. EV71 employs two viral proteases: 2A ...
Ferroptosis is a new form of regulated, nonapoptotic cell death driven by iron-dependent phospholipid peroxidation. Its therapeutic potential is however, greatly limited by the low efficiency of regulating cell ferroptosis in vivo. Herein, we report a PROTAC-based protein degrader that depletes endogenous glutathione peroxidase 4 (GPX4) and induces cancer cell ferroptosis. We demonstrate that a rationally designed GPX4 degrader, dGPX4, can deplete tumor cell GPX4 via proteasomal protein degradation, showing a five-fold enhancement of ferroptosis induction efficiency compared to that of GPX4 inhibition using ML162. Moreover, we show that the intracellular delivery of dGPX4 using biodegradable lipid nanoparticles (
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