Modification Of Chains Research Articles

Design and synthesis of benzofuran- and naphthalene-fused thiazinones as antimycobacterial agents.

Benzothiazinones (BTZs) have widely inspired medicinal chemistry and translational research due to their remarkable antitubercular potency and clinical potential. While most structure-activity relationship campaigns have largely focused on lateral chain modifications and substituents on the BTZ core, scaffold hopping strategies have been rarely investigated previously. In this work, we report the first example of ring expansion of the BTZ core toward benzofuran- and naphthalene-fused thiazinones. In vitro testing showed micromolar activity for both compounds, and molecular docking simulations provided insights into their reduced inhibitory capacity toward the enzymatic target (DprE1). Calculated electrochemical potentials revealed a lower susceptibility to reduction as opposed to BTZ drug candidates, in line with the mechanistic requirement for covalent binding.

Injectable, pore-forming, self-healing, and adhesive hyaluronan hydrogels for soft tissue engineering applications

Most existing injectable hydrogels are non-porous, thereby lacking a microporous structure to promote cell ingrowth. Also, most hydrogels do not effectively adhere to the host tissue. The present study describes an injectable double network hydrogel formed by combining two hyaluronic acid (HA) derivatives, namely dopamine grafted HA (DAHA) and methacrylated HA (HAMA). These constituents instantly form a physically crosslinked network through Fe3+-dopamine coordination, and confer fast gelation, pore formation, and self-healing properties to the hydrogel. Photocroslinked upon UV exposure, HAMA forms a chemically crosslinked network, thereby improving mechanical and degradation properties. The adhesive properties of this hydrogel are attributed to the presence of dopamine groups, inspired by mussel creatures. Proper modification of HA chains was confirmed by NMR spectroscopy. The physical, mechanical, rheological, and biological properties of the new hydrogels were quantified in wet laboratory conditions. The results revealed that the DAHA/HAMA hydrogel rapidly forms a self-healing microporous adhesive scaffold with a 26.9 µm pore size, 29.4 kPa compressive modulus, and 12.8 kPa adhesion strength in under 6 s. These findings suggest that the new hydrogel is a promising candidate for in situ repair of soft tissues, particularly mechanically dynamic ones such as the vocal folds, cartilage, and dermis.

Harnessing Aromatic-Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification.

Peptide engineering efforts have delivered drugs for diverse human diseases. Side chain alteration is among the most common approaches to designing new peptides for specific applications. The peptide backbone can be modified as well, but this strategy has received relatively little attention. Here we show that new and favorable contacts between a His side chain on a target protein and an aromatic side chain on a synthetic peptide ligand can be engineered by rational and coordinated side chain modification and backbone extension. Side chain modification alone was unsuccessful. Binding measurements, high-resolution structural studies and pharmacological outcomes all support the synergy between backbone and side chain modification in engineered ligands of the parathyroid hormone receptor-1, which is targeted by osteoporosis drugs. These results should motivate other structure-based designs featuring coordinated side chain modification and backbone extension to enhance the engagement of peptide ligands with target proteins.

Harnessing Aromatic‐Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification

AbstractPeptide engineering efforts have delivered drugs for diverse human diseases. Side chain alteration is among the most common approaches to designing new peptides for specific applications. The peptide backbone can be modified as well, but this strategy has received relatively little attention. Here we show that new and favorable contacts between a His side chain on a target protein and an aromatic side chain on a synthetic peptide ligand can be engineered by rational and coordinated side chain modification and backbone extension. Side chain modification alone was unsuccessful. Binding measurements, high‐resolution structural studies and pharmacological outcomes all support the synergy between backbone and side chain modification in engineered ligands of the parathyroid hormone receptor‐1, which is targeted by osteoporosis drugs. These results should motivate other structure‐based designs featuring coordinated side chain modification and backbone extension to enhance the engagement of peptide ligands with target proteins.

A DFT Study on the Impact of Saturated and Conjugated Side Chains on the Optoelectronic Performance of Y-series Nonfullerene Acceptors

Organic photovoltaic (OPV) consisting of nonfullerene acceptors have been found to be excellent candidates for harnessing solar energy. Extensive studies are being carried out to modify structures in a number of ways to enhance their efficiency. These include modifications in the acceptor part, use of efficient backbones and insertion of pi spacers. One strategy is the attachment of donor side chains for better assembly of molecules. In this work, the effect of theoretically designed side chains on electrochemical and optical properties of OPVs was studied. A series of molecules consisting of saturated (SC1-4) and conjugated donor (CD1-2) were designed and studied computationally for their potential OPV properties. Parameters like Band gap, absorption spectrum, frontier molecular orbital distribution, binding energy, fill factor, open circuit voltage, excitation energies, density of states (DOS) and transition density matrix (TDM) were studied using DFT and TD-DFT methods. Unsaturated side chains although exhibit better performance in terms of open circuit voltage and hole mobility but reduce light harvesting efficiency. All saturated side chain modifications showed improvement in fill factor and open circuit voltage than reference molecule. SC3 modification with red shift and smaller band gap showed the best performance.

Anti-Toxoplasma gondii Effects of Lipopeptide Derivatives of Lycosin-I.

Toxoplasmosis, caused by Toxoplasma gondii (T. gondii), is a serious zoonotic parasitic disease. We previously found that Lycosin-I exhibited anti-T. gondii activity, but its serum stability was not good enough. In this study, we aimed to improve the stability and activity of Lycosin-I through fatty acid chain modification, so as to find a better anti-T. gondii drug candidate. The α/ε-amino residues of different lysine residues of Lycosin-I were covalently coupled with lauric acid to obtain eight lipopeptides, namely L-C12, L-C12-1, L-C12-2, L-C12-3, L-C12-4, L-C12-5, L-C12-6, and L-C12-7. Among these eight lipopeptides, L-C12 showed the best activity against T. gondii in vitro in a trypan blue assay. We then conjugated a shorter length fatty chain, aminocaproic acid, at the same modification site of L-C12, namely L-an. The anti-T. gondii effects of Lycosin-I, L-C12 and L-an were evaluated via an invasion assay, proliferation assay and plaque assay in vitro. A mouse model acutely infected with T. gondii tachyzoites was established to evaluate their efficacy in vivo. The serum stability of L-C12 and L-an was improved, and they showed comparable or even better activity than Lycosin-I did in inhibiting the invasion and proliferation of tachyzoites. L-an effectively prolonged the survival time of mice acutely infected with T. gondii. These results suggest that appropriate fatty acid chain modification can improve serum stability and enhance anti-T. gondii effect of Lycosin-I. The lipopeptide derivatives of Lycosin-I have potential as a novel anti-T. gondii drug candidate.

Poly(2-oxazoline)-Based Polyplexes as a PEG-Free Plasmid DNA Delivery Platform.

The present study expands the versatility of cationic poly(2-oxazoline) (POx) copolymers as a polyethylene glycol (PEG)-free platform for gene delivery to immune cells, such as monocytes and macrophages. Several block copolymers are developed by varying nonionic hydrophilic blocks (poly(2-methyl-2-oxazoline) (pMeOx) or poly(2-ethyl-2-oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2-isopropyl-2-oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2-methoxy-carboxyethyl-2-oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2-aminoethyl)amine (TREN). For the attachment of a targeting ligand, mannose, azide-alkyne cycloaddition click chemistry methods are employed. Of the two cationic side chains, polyplexes made with DET-containing copolymers transfect macrophages significantly better than those made with TREN-based copolymer. Likewise, nontargeted pEtOx-based diblock copolymer is more active in cell transfection than pMeOx-based copolymer. The triblock copolymer with hydrophobic block iPrOx performs poorly compared to the diblock copolymer which lacks this additional block. Surprisingly, attachment of a mannose ligand to either copolymer is inhibitory for transfection. Despite similarities in size and design, mannosylated polyplexes result in lower cell internalization compared to nonmannosylated polyplexes. Thus, PEG-free, nontargeted DET-, and pEtOx-based diblock copolymer outperforms other studied structures in the transfection of macrophages and displays transfection levels comparable to GeneJuice, a commercial nonlipid transfection reagent.

Cabazitaxel prodrug nanoassemblies with branched chain modifications: Narrowing the gap between efficacy and safety

The clinical application of cabazitaxel (CTX) is restricted by severe dose-related toxicity, failing to considering therapeutic efficacy and safety together. Self-assembled prodrugs promote new drug delivery paradigms as they can self-deliver and self-formulate. However, the current studies mainly focused on the use of straight chains to construct self-assembled prodrugs, and the role of branched chains in prodrug nanoassemblies remains to be clarified. In this study, we systematically explored the structure–function relationship of prodrug nanoassemblies using four CTX prodrugs that contained branched chain aliphatic alcohols (BAs) with different alkyl lengths. Overall, CTX-SS-BA20 NPs with the proper alkyl length exhibited significant improvements in both antitumor efficacy and biosafety. Furthermore, compared with straight chain (SC) modified prodrug nanoassemblies (CTX-SS-SC20 NPs), CTX-SS-BA20 NPs still hold great therapeutic promise due to its good biosafety. These findings illustrated the significance of BAs as modified chains in designing prodrug nanoassemblies for narrowing the efficacy-to-safety gap of cancer therapy.

Synthesis and Insecticidal Activity Study of Azidopyridryl Containing Dichlorolpropene Ether Derivatives.

Pyridalyl, as a novel insecticide with an unknown mode of action, has shown excellent control efficacy against lepidopterous larvae and thrips. Previous modifications of this compound have mostly focused on the pyridine moiety, with limited information available about modifications to other parts of pyridalyl. In this paper, we report the synthesis and insecticidal activity of a series of azidopyridryl-containing dichlorolpropene ether derivatives, based on modifications to the middle alkyl chain of pyridalyl. Screening results for insecticidal activity indicate that our synthesized compounds show moderate to high activities at the tested concentrations against P. xylostella. Particularly, compound III-10 exhibits a LC50 value of 0.831 mg L-1, compared to the LC50 value of pyridalyl at 2.021 mg L-1. Furthermore, compound III-10 also displays a relatively broad insecticidal spectrum against Lepidoptera pests M. separata, C. suppressalis, O. nubilalis, and C. medinalis. Finally, in field trials, III-10 demonstrates better control efficiency against Chilo suppressalis compared to pyridalyl. Overall, our findings suggest that the modification of the middle alkyl chain of pyridalyl may be a promising approach for developing insecticides with improved efficacy.

Characterization of Coating Films of Thixotropic Solvent Gel Containing Organo‐modified Nanodiamonds

AbstractA gelation solvent containing a diamide‐based thixotropic additive with two hydrocarbons and organo‐modified nanodiamonds was prepared and evaluated herein as a coating film. Nanodiamonds were introduced into a solvent containing diamide‐based thixotropic additive molecules with 12‐hydroxystearyl chains which were uniformly dispersed due to organic chain modification on the outermost layer surface. In addition to common solvents including toluene, ethyl cetyl hexanoate, a cosmetic emollient, forms nanodiamond‐containing gels. The helical nanofibers formed by the diamide‐based thixotropic additive molecule with two hydrocarbons in the gel showed affinity for the organo‐modified nanodiamonds, and the contact morphology between the nanofibers and nanodiamond particles was confirmed. Nanodiamonds exhibited a denaturation effect on biomolecules adsorbed on their surfaces. Overall, nanodiamond‐containing emollient gels are expected to exhibit antibacterial properties against viruses and malodorous bacteria on skin as part of thixotropic immobilization films for cosmetic powders.

Disulfide-incorporated lipid prodrugs of cidofovir: Synthesis, antiviral activity, and release mechanism

The double-stranded DNA (dsDNA) viruses represented by adenovirus and monkeypox virus, have attracted widespread attention due to their high infectivity. In 2022, the global outbreak of mpox (or monkeypox) has led to the declaration of a Public Health Emergency of International Concern. However, to date therapeutics approved for dsDNA virus infections remain limited and there are still no available treatments for some of these diseases. The development of new therapies for treating dsDNA infection is in urgent need. In this study, we designed and synthesized a series of novel disulfide-incorporated lipid conjugates of cidofovir (CDV) as potential candidates against dsDNA viruses including vaccinia virus (VACV) and adenovirus (AdV) 5. The structure-activity relationship analyses revealed that the optimum linker moiety was C2H4 and the optimum aliphatic chain length was 18 or 20 atoms. Among the synthesized conjugates, 1c exhibited more potency against VACV (IC50 = 0.0960 μM in Vero cells; IC50 = 0.0790 μM in A549 cells) and AdV5 (IC50 = 0.1572 μM in A549 cells) than brincidofovir (BCV). The transmission electron microscopy (TEM) images revealed that the conjugates could form micelles in phosphate buffer. The stability studies in the GSH environment demonstrated that the formation of micelles in phosphate buffer might protect the disulfide bond from glutathione (GSH) reduction. The dominant means of the synthetic conjugates to liberate the parent drug CDV was by enzymatic hydrolysis. Furthermore, the synthetic conjugates remained sufficiently stable in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and pooled human plasma, which indicated the possibility for oral administration. These results indicated 1c may be a broad-spectrum antiviral candidate against dsDNA viruses with potential oral administration. Moreover, modification of the aliphatic chain attached to the nucleoside phosphonate group was involved as an efficient prodrug strategy for the development of potent antiviral candidates.

PEGylated pH-responsive peptide-mRNA nano self-assemblies enhance the pulmonary delivery efficiency and safety of aerosolized mRNA

Inhalable messenger RNA (mRNA) has demonstrated great potential in therapy and vaccine development to confront various lung diseases. However, few gene vectors could overcome the airway mucus and intracellular barriers for successful pulmonary mRNA delivery. Apart from the low pulmonary gene delivery efficiency, nonnegligible toxicity is another common problem that impedes the clinical application of many non-viral vectors. PEGylated cationic peptide-based mRNA delivery vector is a prospective approach to enhance the pulmonary delivery efficacy and safety of aerosolized mRNA by oral inhalation administration. In this study, different lengths of hydrophilic PEG chains were covalently linked to an amphiphilic, water-soluble pH-responsive peptide, and the peptide/mRNA nano self-assemblies were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro mRNA binding and release, cellular uptake, transfection, and cytotoxicity were studied, and finally, a proper PEGylated peptide with enhanced pulmonary mRNA delivery efficiency and improved safety in mice was identified. These results showed that a proper N-terminus PEGylation strategy using 12-monomer linear monodisperse PEG could significantly improve the mRNA transfection efficiency and biocompatibility of the non-PEGylated cationic peptide carrier, while a longer PEG chain modification adversely decreased the cellular uptake and transfection on A549 and HepG2 cells, emphasizing the importance of a proper PEG chain length selection. Moreover, the optimized PEGylated peptide showed a significantly enhanced mRNA pulmonary delivery efficiency and ameliorated safety profiles over the non-PEGylated peptide and LipofectamineTM 2000 in mice. Our results reveal that the PEGylated peptide could be a promising mRNA delivery vector candidate for inhaled mRNA vaccines and therapeutic applications for the prevention and treatment of different respiratory diseases in the future.

Combining Chemical Protein Synthesis and Random Nonstandard Peptides Integrated Discovery for Modulating Biological Processes.

ConspectusChemical manipulation of naturally occurring peptides offers a convenient route for generating analogs to screen against different therapeutic targets. However, the limited success of the conventional chemical libraries has urged chemical biologists to adopt alternative methods such as phage and mRNA displays and create libraries of a large number of variants for the screening and selection of novel peptides. Messenger RNA (mRNA) display provides great advantages in terms of the library size and the straightforward recovery of the selected polypeptide sequences. Importantly, the integration of the flexible in vitro translation (FIT) system with the mRNA display provides the basis of the random nonstandard peptides integrated discovery (RaPID) approach for the introduction of diverse nonstandard motifs, such as unnatural side chains and backbone modifications. This platform allows the discovery of functionalized peptides with tight binding against virtually any protein of interest (POI) and therefore shows great potential in the pharmaceutical industry. However, this method has been limited to targets generated by recombinant expression, excluding its applications to uniquely modified proteins, particularly those with post-translational modifications.Chemical protein synthesis allows a wide range of changes to the protein's chemical composition to be performed, including side chain and backbone modifications and access to post-translationally modified proteins, which are often inaccessible or difficult to achieve via recombinant expression methods. Notably, d-proteins can be prepared via chemical synthesis, which has been used in mirror image phase display for the discovery of nonproteolytic d-peptide binders.Combining chemical protein synthesis with the RaPID system allows the production of a library of trillions of cyclic peptides and subsequent selection for novel cyclic peptide binders targeting a uniquely modified protein to assist in studying its unexplored biology and possibly the discovery of new drug candidates.Interestingly, the small post-translational modifier protein ubiquitin (Ub), with its various polymeric forms, regulates directly or indirectly many biochemical processes, e.g., proteasomal degradation, DNA damage repair, cell cycle regulation, etc. In this Account, we discuss combining the RaPID approach against various synthetic Ub chains for selecting effective and specific macrocyclic peptide binders. This offers an advancement in modulating central Ub pathways and provides opportunities in drug discovery areas associated with Ub signaling. We highlight experimental approaches and conceptual adaptations required to design and modulate the activity of Lys48- and Lys63-linked Ub chains by macrocyclic peptides. We also present the applications of these approaches to shed light on related biological activities and ultimately their activity against cancer. Finally, we contemplate future developments still pending in this exciting multidisciplinary field.

Adapting R4 simplifications of Anaerobic Digestion Model No. 1 (ADM1-R4) for pump-mixed biogas production

Modification of the production chain in biogas generation is a common tactic used in this industry. However, the selection of appropriate reactor configuration and operational parameters is a crucial task. In such cases, mathematical modeling provides great support. Herein, we adapted a simplified version of the Anaerobic Digestion Model No. 1 to a system in which the mechanical stirrer was replaced with an external pump that recirculated the reactor content. Despite having conceptual similarities with continuous stirred-tank reactors, this system exhibited considerable differences in the vertical distribution inside the tank. The model was optimized by using a “genetic algorithm” and “fmincon” function to test both approaches. The new model showed very high accuracy with a mean error of 5.9–9.8%, depending on the mixing intensity, whereas the previous reference models reached 19.7% error. Therefore, compared to the previous models, the simplification of the ordinary differential equation in our new model did not significantly decrease accuracy; in fact, the precision was even higher than before in some cases. Finally, the new model was practically applied to demonstrate its implementation in realistic scenarios.

Unveiling the Role of Capping Groups in Naphthalene N-Capped Dehydrodipeptide Hydrogels.

Self-assembled peptide-based hydrogels are archetypical nanostructured materials with a plethora of foreseeable applications in nanomedicine and as biomaterials. N-protected di- and tri-peptides are effective minimalist (molecular) hydrogelators. Independent variation of the capping group, peptide sequence and side chain modifications allows a wide chemical space to be explored and hydrogel properties to be tuned. In this work, we report the synthesis of a focused library of dehydrodipeptides N-protected with 1-naphthoyl and 2-naphthylacetyl groups. The 2-naphthylacetyl group was extensively reported for preparation of peptide-based self-assembled hydrogels, whereas the 1-naphthaloyl group was largely overlooked, owing presumably to the lack of a methylene linker between the naphthalene aromatic ring and the peptide backbone. Interestingly, dehydrodipeptides N-capped with the 1-naphthyl moiety afford stronger gels, at lower concentrations, than the 2-naphthylacetyl-capped dehydrodipeptides. Fluorescence and circular dichroism spectroscopy showed that the self-assembly of the dehydrodipeptides is driven by intermolecular aromatic π-π stacking interactions. Molecular dynamics simulations revealed that the 1-naphthoyl group allows higher order aromatic π-π stacking of the peptide molecules than the 2-naphthylacetyl group, together with hydrogen bonding of the peptide scaffold. The nanostructure of the gel networks was studied by TEM and STEM microscopy and was found to correlate well with the elasticity of the gels. This study contributes to understanding the interplay between peptide and capping group structure on the formation of self-assembled low-molecular-weight peptide hydrogels. Moreover, the results presented here add the 1-naphthoyl group to the palette of capping groups available for the preparation of efficacious low-molecular-weight peptide-based hydrogels.

Synthesis and Characterization of Multi-Reducing-End Polysaccharides.

Site-specific modification is a great challenge for polysaccharide scientists. Chemo- and regioselective modification of polysaccharide chains can provide many useful natural-based materials and help us illuminate fundamental structure-property relationships of polysaccharide derivatives. The hemiacetal reducing end of a polysaccharide is in equilibrium with its ring-opened aldehyde form, making it the most uniquely reactive site on the polysaccharide molecule, ideal for regioselective decoration such as imine formation. However, all natural polysaccharides, whether they are branched or not, have only one reducing end per chain, which means that only one aldehyde-reactive substituent can be added. We introduce a new approach to selective functionalization of polysaccharides as an entrée to useful materials, appending multiple reducing ends to each polysaccharide molecule. Herein, we reduce the approach to practice using amide formation. Amine groups on monosaccharides such as glucosamine or galactosamine can react with carboxyl groups of polysaccharides, whether natural uronic acids like alginates, or derivatives with carboxyl-containing substituents such as carboxymethyl cellulose (CMC) or carboxymethyl dextran (CMD). Amide formation is assisted using the coupling agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM). By linking the C2 amines of monosaccharides to polysaccharides in this way, a new class of polysaccharide derivatives possessing many reducing ends can be obtained. We refer to this class of derivatives as multi-reducing-end polysaccharides (MREPs). This new family of derivatives creates the potential for designing polysaccharide-based materials with many potential applications, including in hydrogels, block copolymers, prodrugs, and as reactive intermediates for other derivatives.

Influence of monohalogenated flexible tails on the mesomorphism of triphenylene-based discotics

A series of triphenylene-based discotic liquid crystals (DLCs) modified by fluorination or chlorination at the end of peripheral flexible chains were examined in this work. DLC derivatives containing one mono fluorine or chlorine-substituted flexible chain 4a-e and six mono fluorine or chlorine-substituted flexible chains 8a & 8b, 10a & 10b were mainly synthesized and molecular structures confirmed by 1H NMR, 19F NMR and MALDI-TOF MS. The mesogenic properties of the obtained compounds were further studied by differential scanning calorimetry (DSC), polarizing optical microscopy (POM) and X-ray diffraction (XRD). Impressively, compounds 4a-e were found exhibiting hexagonal columnar phases and the π-π stacking distances of 4a-e were lower than that of the parent molecule HAT5. Due to the influence of atomic radius and molecular symmetry, the mesophase stability of the fluorinated triphenylene compounds was greater than the chlorinated ones. Through the modification of the side chain, the self-assembly behavior of triphenylene was stronger and the intracolumnar distance was decreased, which may give rise to a higher charge transport mobility. Compound 10b showed self-assembly behavior and formed a spherulite texture that could also remain orderly until room temperature. This is rare in reported DLCs and it might be applied as active components of in electronic devices. These ordered stacked discotic molecules may exhibit improved charge carrier mobility as semiconducting materials.

ISG15 targets glycosylated PD-L1 and promotes its degradation to enhance antitumor immune effects in lung adenocarcinoma

BackgroundImmunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown.MethodsThe relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues.ResultsISG15 promotes the infiltration of CD4+ T lymphocytes. In vivo and in vitro experiments demonstrated that ISG15 induces CD4+ T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCLC tissues. In addition, reduced accumulation of PD-L1 by ISG15 in mice also increased splenic lymphocyte infiltration as well as promoted cytotoxic T cell infiltration in the tumor microenvironment, thereby enhancing anti-tumor immunity.ConclusionsThe ubiquitination modification of PD-L1 by ISG15 increases K48-linked ubiquitin chain modification, thereby increasing the degradation rate of glycosylated PD-L1-targeted proteasome pathway. More importantly, ISG15 enhanced the sensitivity to immunosuppressive therapy. Our study shows that ISG15, as a post-translational modifier of PD-L1, reduces the stability of PD-L1 and may be a potential therapeutic target for cancer immunotherapy.

Conformation Flipping of Asymmetric Nonfullerene Acceptors Enabling High‐Performance Organic Solar Cells with 77% Fill Factors

Considerable progress on high‐performance organic solar cells (OSCs) has been achieved in the past due to the rapid development of nonfullerene acceptors (NFAs). Typically, two kinds of methods have been employed to manipulate energy levels and aggregation of NFAs, i.e., molecular engineering on alkyl side chains and modification of the heterocyclic rings in the backbone. Herein, a novel asymmetric thiophene[3,2‐b] pyrrole (TP)‐based NFA with flipped molecular conformation, named as PTBTT‐4F, is designed and synthesized. The introduction of the pyrrole ring in the novel NFA would not only afford extra reaction sites for side chain modification, but also induce substantial intramolecular charge transfer, thus leading to elevated energy levels of the NFA and thereby lower energy loss of the OSCs. When pairing with polymer donor PBDB‐TF to fabricate OSCs, concurrent improvement in open‐circuit voltage, short‐circuit current (JSC), and fill factor (FF) is realized, which delivers an outstanding power conversion efficiency (PCE) of 14.49%. Benefitting from effective molecular stacking and optimized phase separation induced by molecular conformation variation, asymmetric PTBTT‐4F fabricated OSCs exhibit much higher JSCs and FFs than the symmetrical PTBTP‐4F devices.

The dynamic architecture of Map1- and NatB-ribosome complexes coordinates the sequential modifications of nascent polypeptide chains.

Cotranslational modification of the nascent polypeptide chain is one of the first events during the birth of a new protein. In eukaryotes, methionine aminopeptidases (MetAPs) cleave off the starter methionine, whereas N-acetyl-transferases (NATs) catalyze N-terminal acetylation. MetAPs and NATs compete with other cotranslationally acting chaperones, such as ribosome-associated complex (RAC), protein targeting and translocation factors (SRP and Sec61) for binding sites at the ribosomal tunnel exit. Yet, whereas well-resolved structures for ribosome-bound RAC, SRP and Sec61, are available, structural information on the mode of ribosome interaction of eukaryotic MetAPs or of the five cotranslationally active NATs is only available for NatA. Here, we present cryo-EM structures of yeast Map1 and NatB bound to ribosome-nascent chain complexes. Map1 is mainly associated with the dynamic rRNA expansion segment ES27a, thereby kept at an ideal position below the tunnel exit to act on the emerging substrate nascent chain. For NatB, we observe two copies of the NatB complex. NatB-1 binds directly below the tunnel exit, again involving ES27a, and NatB-2 is located below the second universal adapter site (eL31 and uL22). The binding mode of the two NatB complexes on the ribosome differs but overlaps with that of NatA and Map1, implying that NatB binds exclusively to the tunnel exit. We further observe that ES27a adopts distinct conformations when bound to NatA, NatB, or Map1, together suggesting a contribution to the coordination of a sequential activity of these factors on the emerging nascent chain at the ribosomal exit tunnel.