Assembly of Covalently Inorganic-Organic Hybrid Molecular Framework Based on Porphyrin and Phthalocyanine Derivatives—Sensitizer for Dye Sensitized Solar Cells

The research on sensitizer for dye sensitized solar cells based on (metallo)porphyrin/phthalocyanine materials were reviewed, and experimental design and assembly method were advised. Latest progress and research status of sensitizer dyes based on metalloporphyrins applied in dye sensitized solar cells was summarized. The preparation and construction of sensitizer electrodes and dye sensitized solar cells based on metal organic frameworks (MOFs) of (metallo)porphyrin/phthalocyanine were projected.

Preparation of Single Substituted Phenyl Porphyrins Form <i>Meso</i>-Tetraphenyl Porphyrin-Synthetic Example from Symmetric Porphyrin into Asymmetric Porphyrins

Two asymmetric porphyrins, 5-(4-chloromethylphenyl)-10, 15, 20-triphenyl porphyrin and 5-(4-formylphenyl)-10, 15, 20-triphenyl porphyrin, were successfully prepared by the symmetric meso-tetraphenyl porphyrin and relative molecular configurations and properties were characterized by spectral determinations. This work presented an example for synthesis of asymmetric porphyrin derivatives from the symmetric porphyrin. Both asymmetric porphyrins are reactive in molecular assembly, the concerned reactions including alkylation with Grignard reagents, etherification with alcohols, aldol condensation and Mannich reaction for modification and enhancing their functionality. In this work, the reaction conditions were improved, synthetic strategy and route were confirmed.

Preparation of N, N, N′, N′-tetrakis-(2-benzimidazolylmethyl)-1,2-ethanediamine and crystal assemblies of the relative complexes

N, N, N′, N′-tetrakis-(2-benzimidazolylmethyl)-1, 2-ethanediamine(TBIMEDA), was prepared by reaction of ethylenediamine tetra-acetic acid disodium salt(EDTA) with 1, 2-diaminobenzene in a refluxed glycol solution, and furthermore, three allomeric complexes[(MIITBIMEDA) SO4·5H2O, M = Cd, Co, Ni] were selfassembled by solvothermal method based on reaction of this ligand with the relative sulfates respectively. These allomeric complexes were characterized by elemental analysis and IR spectroscopy and their crystal structures were determined by single crystal X-ray structural analysis. In the crystal architecture of these complexes, every metal(II) ion is chelated by one neutral TBIMEDA ligand to form an octahedral core with configuration of five heterocyclic rings (five- member ring). These cores then were linked to- gether by multi hydrogen bond interactions with sul- fate ions and water molecules to construct their 3D crystal architectures.

Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-II.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ production.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy

The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8^(+)T cell-mediated cytotoxicity.Immune checkpoint blockade(ICB)could induce tumor ferroptosis through IFN-γreleased by immune cells,indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor growth.However,the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored yet.In this study,the small molecule Hemin that could bind withTIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking assay.Hemin could effectively restore the IL-2 secretion from Jurkat-hTIGIT cells.Hemin reinvigorated the function of CD8^(+)T cells to secrete IFN-γand the elevated IFN-γcould synergize with Hemin to induce ferroptosis in tumor cells.Hemin inhibited tumor growth by boosting CD8^(+)T cell immune response and inducing ferroptosis in CT26 tumor model.More importantly,Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor model.In summary,our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell ferroptosis,which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

Identification and optimization of peptide inhibitors to block VISTA/PSGL-1 interaction for cancer immunotherapy

Developing new therapeutic agents for cancer immunotherapy is highly demanding due to the low response ratio of PD-1/PD-L1 blockade in cancer patients.Here,we discovered that the novel immune checkpoint VISTA is highly expressed on a variety of tumor-infiltrating immune cells,especially myeloid derived suppressor cells(MDSCs)and CD8^(+)T cells.Then,peptide C1 with binding affinity to VISTA was developed by phage displayed bio-panning technique,and its mutant peptide VS3 was obtained by molecular docking based mutation.Peptide VS3 could bind VISTA with high affinity and block its interaction with ligand PSGL-1 under acidic condition,and elicit anti-tumor activity in vivo.The peptide DVS3-Pal was further designed by D-amino acid substitution and fatty acid modification,which exhibited strong proteolytic stability and significant anti-tumor activity through enhancing CD8^(+)T cell function and decreasing MDSCs infiltration.This is the first study to develop peptides to block VISTA/PSGL-1 interaction,which could act as promising candidates for cancer immunotherapy.

Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression via AKT/GSK3β/IL-8 signaling pathway

Tryptophan 2,3-dioxygnease 2(TDO2) is specific for metabolizing tryptophan to kynurenine(KYN),which plays a critical role in mediating immune escape of cancer.Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers,its tumor-promoting role in esophageal squamous cell carcinoma(ESCC) remains unclear.Here,we observed that TDO2 was overexpressed in ESCC tis sues and correlated significantly with lymph node metastasis,advanced clinical stage,and unfavorable prognosis.Functional experiments showed that TDO2 promoted tumor cell proliferation,migration,and colony formation,which could be prevented by inhibition of TDO2 and aryl hydrocarb on receptor(AHR).Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model,tumor burden of C57 BL/6 mice with ESCC induced by 4-NQO,enhance the expression of phosphorylated AKT,with subsequent pho sphorylation of GSK3β,and polarization of M2 macrophages by upregulating interleukin-8(IL-8) to accelerate tumor progression in the tumor microenvironment(TME).Collectively,our results discovered that TDO2 could upregulate IL-8 through AKT/GSK3β to direct the polarization of M2 macrophages in ESCC,and suggested that TDO2 could represent as an attractive therapeutic target and prognostic marker to ESCC.

A multifunctional cross-validation high-throughput screening protocol enabling the discovery of new SHP2 inhibitors

The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2(SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2(SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76 A. After initial screening of our in-house compound library(w2300 compounds), we identified 4 new SHP2-PTP inhibitors(0.17%hit rate) and 28 novel allosteric SHP2 inhibitors(1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP(SYK-85: IC_(50) Z 0.32 mmol/L;WS-635: IC_(50) Z 4.13 mmol/L) and thus represent novel scaffolds for designing new SHP2-PTP inhibitors. TK-147, an allosteric inhibitor, inhibited SHP2 potently(IC_(50) Z 0.25 mmol/L). In structure, TK-147 could be regarded as a bioisostere of the well characterized SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2. The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins.

Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer

Colorectal cancer has one of the highest mortality rates among malignant tumors,and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint inhibitors.Identification of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer immunotherapy.Here,we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumorspecific cytotoxic T cell responses.Three HLA-A2-restricted neoepitopes (P31,P50,and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer patients.Cytotoxic T lymphocytes induced in HLA-A2.1/K^(b) transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2^(+) cancer cells.Adoptive transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 antibody.These results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal cancer.The combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors,such as anti-PD-1,could provide a promising treatment strategy for non-MSI-H colorectal cancer.