Anti-tumor effects of p53N15-based fusion peptide in the transfected H1299 lung cancer cells

Objective Loss-of-function mutation of p53,a tumor suppressor gene,is an important mechanism for the development of human cancers. In this study we tried to transfect p53N15-based fusion peptide into H1299,a lung cancer cell line,and evaluate the anti-tumor effects of the fusion peptide. Methods Adeno-associated virus (AAV) vectors were used for transfecting p53N15 fusion peptide into p53-null lung adenocarcinoma H1299 cells.

Coarse Grained Molecular Dynamics Simulation of Interaction between Hemagglutinin Fusion Peptides and Lipid Bilayer Membranes

Microscopic level interaction between fusion-peptides and lipid bilayer membranes plays a crucial role in membrane fusion,a key step of viral infection.In this paper,we use coarse-grained molecular dynamics(CGMD)simulations to study the interaction between hemagglutinin fusion-peptides and phospholipid bilayer membranes.With CGMD,we are able to simulate the interaction of fusion peptides with a relatively large piece of membrane for a sufficiently long time period,which is necessary for a detailed understanding of the fusion process.A conformation of the peptide with a kink at the level of phosphate group is obtained,consistent with NMR and EPR studies.Our results show that the N-terminal segment of the peptide inserts more deeply into the membrane bilayer compared to the C-terminal segment,as observed in previous experiments.Our simulations also show that the presence of fusion peptides inside the membrane may cause bilayer thinning and lipid molecule disorder.Finally,our results reveal that peptides tend to aggregate,indicating cluster formation as seen in many experiments.

A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery

Coronaviruses(Co Vs)have brought serious threats to humans,particularly severe acute respiratory syndrome coronavirus 2(SARS-Co V-2),which continually evolves into multiple variants.These variants,especially Omicron,reportedly escape therapeutic antibodies and vaccines,indicating an urgent need for new antivirals with pan-SARS-Co V-2 inhibitory activity.We previously reported that a peptide fusion inhibitor,P3,targeting heptad repeated-1(HR1)of SARS-Co V-2 spike(S)protein,could inhibit viral infections.Here,we further designed multiple derivatives of the P3 based on structural analysis and found that one derivative,the P315V3,showed the most efficient antiviral activity against SARS-Co V-2 variants and several other sarbecoviruses,as well as other human-Co Vs(HCo Vs).P315V3 also exhibited effective prophylactic efficacy against the SARS-Co V-2 Delta and Omicron variants in mice via intranasal administration.These results suggest that P315V3,which is in PhaseⅡclinical trial,is promising for further development as a nasal pan-SARS-Co V-2 or pan-Co Vs inhibitor to prevent or treat CoV diseases.

Recombinant adeno-associated virus delivered human thioredoxin-PR39 prevents hypoxia-induced apoptosis of ECV304 cells

Human thioredoxin and antibacterial peptide, PR39, have been shown to have potent antioxidant effects that may prolong survival of cells during hypoxia. The pSSCMV/human thioredoxin-PR39 vector was successfully constructed in this study and used to infect ECV304 cells. Transfected ECV304 cells were incubated at 1%, 5% hypoxic, and normal oxygen conditions. We found that the number of apoptotic cells after transfection with recombinant adeno-associated virus-human thioredoxin -PR39 was significantly lower than controls, suggesting a protective effect of the recombinant human thioredoxin-PR39 protein on hypoxic cells.

Escape from abluminal LRP1-mediated clearance for boosted nanoparticle brain delivery and brain metastasis treatment

Breast cancer brain metastases(BCBMs)are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth.Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable bloodbrain barrier(BBB).Accumulation studies prove that low density lipoprotein receptor-related protein 1(LRP1)is promising target for BBB transcytosis.However,as the primary clearance receptor for amyloid beta and tissue plasminogen activator,LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics.Matrix metalloproteinase-1(MMP1)is highly enriched in metastatic niche to promote growth of BCBMs.Herein,it is reported that nanoparticles(NPs-K-s-A)tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2(A),can surmount the BBB and escape LRP1-mediated clearance in metastatic niche.NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice,while comparable brain accumulation in normal mice.The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs.Due to the efficient BBB penetration,special and remarkable clearance escape,and facilitated therapeutic outcome,the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.