Room-temperature multiple ligands-tailored SnO2 quantum dots endow in situ dual-interface binding for upscaling efficient perovskite photovoltaics with high VOC

The benchmark tin oxide (SnO2) electron transporting layers (ETLs) have enabled remarkable progress in planar perovskite solar cell (PSCs). However, the energy loss is still a challenge due to the lack of “hidden interface” control. We report a novel ligand-tailored ultrafine SnO2 quantum dots (QDs) via a facile rapid room temperature synthesis. Importantly, the ligand-tailored SnO2 QDs ETL with multi-functional terminal groups in situ refines the buried interfaces with both the perovskite and transparent electrode via enhanced interface binding and perovskite passivation. These novel ETLs induce synergistic effects of physical and chemical interfacial modulation and preferred perovskite crystallization-directing, delivering reduced interface defects, suppressed non-radiative recombination and elongated charge carrier lifetime. Power conversion efficiency (PCE) of 23.02% (0.04 cm2) and 21.6% (0.98 cm2, VOC loss: 0.336 V) have been achieved for the blade-coated PSCs (1.54 eV Eg) with our new ETLs, representing a record for SnO2 based blade-coated PSCs. Moreover, a substantially enhanced PCE (VOC) from 20.4% (1.15 V) to 22.8% (1.24 V, 90 mV higher VOC, 0.04 cm2 device) in the blade-coated 1.61 eV PSCs system, via replacing the benchmark commercial colloidal SnO2 with our new ETLs.

Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site

Although myriad protein–protein interactions in nature use polyvalent binding, in which multiple ligands on one entity bind to multiple receptors on another, to date an affinity advantage of polyvalent binding has been demonstrated experimentally only in cases where the target receptor molecules are clustered prior to complex formation. Here, we demonstrate cooperativity in binding affinity (i.e., avidity) for a protein complex in which an engineered dimer of the amyloid precursor protein inhibitor (APPI), possessing two fully functional inhibitory loops, interacts with mesotrypsin, a soluble monomeric protein that does not self-associate or cluster spontaneously. We found that each inhibitory loop of the purified APPI homodimer was over three-fold more potent than the corresponding loop in the monovalent APPI inhibitor. This observation is consistent with a suggested mechanism whereby the two APPI loops in the homodimer simultaneously and reversibly bind two corresponding mesotrypsin monomers to mediate mesotrypsin dimerization. We propose a simple model for such dimerization that quantitatively explains the observed cooperativity in binding affinity. Binding cooperativity in this system reveals that the valency of ligands may affect avidity in protein–protein interactions including those of targets that are not surface-anchored and do not self-associate spontaneously. In this scenario, avidity may be explained by the enhanced concentration of ligand binding sites in proximity to the monomeric target, which may favor rebinding of the multiple ligand binding sites with the receptor molecules upon dissociation of the protein complex.

235 Novel biparatopic TIM-3 antibody effectively blocks multiple inherent ligands and activates anti-tumor immunity

BackgroundT cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is a part of modules expressed on dysfunctional or exhausted T cells as well as dendritic cells and has emerged as a target for several therapeutic antibodies that are under clinical development. Co-blockade of TIM-3 and PD-1 results in tumor regression in preclinical models and improves anticancer T cell responses in patients with advanced cancers. TIM-3 has been reported to have multiple ligands including galectin-9, phosphatidylserine, CEACAM-1 and HMGB1, which bind to different regions on the extracellular domain of TIM-3. Most of the TIM-3 antibodies developed to date are intended to inhibit phosphatidylserine that binds to the pocket in TIM-3 immunoglobulin V domain. Galectin-9 binds to carbohydrate motifs on the opposite side of phosphatidylserine-binding site in immunoglobulin V domain and thereby induces cell death in TIM-3+ T cells. We report herein novel antibodies that block TIM-3 binding to multiple ligands including these two important ligands simultaneously.MethodsAnti-TIM-3 antibodies were generated by immunizing mice with a purified recombinant TIM-3 protein and TIM-3-expressing mammalian cell line. Phage display libraries were constructed using cDNAs of splenocytes and lymph node cells of the immunized mice, then subjected to the biopanning using recombinant TIM-3 proteins. After analyzing specificities and affinities to the TIM-3 protein, scFvs obtained were classified by epitope bin and inhibitory effects on TIM-3 binding to the multiple ligands. The scFvs were converted to scFv-Fc to generate biparatopic (bispecific) antibodies.ResultsAt least five classes of TIM-3 antibodies were obtained, and each class was grouped into different epitope bins and has unique inhibitory profiles for multiple ligands of TIM-3. Their biparatopic (bispecific) forms were produced from the scFv clones and subjected to the analyses of TIM-3 binding, inhibition of ligand binding, and immune activation. As expected, the biparatopic antibodies that recognize two different epitopes showed higher affinity and specificity to TIM-3 than monospecific forms. A lead biparatopic antibody that block the binding of TIM-3 to galectin-9 and phosphatidylserine showed remarkable potency on T cell activation, protection from exhaustion and apoptotic cell death of T cells as well as more potent anti-tumor efficacy.ConclusionsThis study demonstrates the successful development of a novel biparatopic antibody that blocks the binding of TIM-3 to phosphatidylserine and galectin-9 simultaneously. The antibody shows the advantages over conventional TIM-3 antibodies in reducing T cell exhaustion and potentially manipulated for the development of human monoclonal antibodies for therapeutic treatment of cancer.

Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or designed multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10–20 years, as potential therapeutic solutions for diseases of complex etiology and diseases with significant drug-resistance problems. Such agents that modulate multiple targets simultaneously are developed with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target or to combinations of single-target drugs. Although this strategy has been proposed for epilepsy therapy >25 years ago, to my knowledge, only one antiseizure medication (ASM), padsevonil, has been intentionally developed as a single molecular entity that could target two different mechanisms. This novel drug exhibited promising effects in numerous preclinical models of difficult-to-treat seizures. However, in a recent randomized placebo-controlled phase IIb add-on trial in treatment-resistant focal epilepsy patients, padsevonil did not separate from placebo in its primary endpoints. At about the same time, a novel ASM, cenobamate, exhibited efficacy in several randomized controlled trials in such patients that far surpassed the efficacy of any other of the newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening and its presumed dual mechanism of action was only described recently. In this review, I will survey the efficacy of single-target vs. multi-target drugs vs. combinations of drugs with multiple targets in the treatment and prevention of epilepsy. Most clinically approved ASMs already act at multiple targets, but it will be important to identify and validate new target combinations that are more effective in drug-resistant epilepsy and eventually may prevent the development or progression of epilepsy.

Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.

AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings

<pre>AutoDock Vina is arguably one of the fastest and most widely used open-source docking engines. However, compared to other docking engines in the AutoDock Suite, it lacks features that support modeling of specific systems such as macrocycles or modeling water explicitly. Here, we describe the implementation of these functionality in AutoDock Vina 1.2.0. Additionally, AutoDock Vina 1.2.0 supports the AutoDock4.2 scoring function, simultaneous docking of multiple ligands, and a batch mode for docking a large number of ligands. Furthermore, we implemented Python bindings to facilitate scripting and the development of docking workflows. This work is an effort toward the unification of the features of the AutoDock4 and AutoDock Vina docking engines. The source code is available at <a href="https://github.com/ccsb-scripps/AutoDock-Vina" rel="noopener noreferrer" target="_blank">https://github.com/ccsb-scripps/AutoDock-Vina</a></pre>

AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings

<pre>AutoDock Vina is arguably one of the fastest and most widely used open-source docking engines. However, compared to other docking engines in the AutoDock Suite, it lacks features that support modeling of specific systems such as macrocycles or modeling water explicitly. Here, we describe the implementation of these functionality in AutoDock Vina 1.2.0. Additionally, AutoDock Vina 1.2.0 supports the AutoDock4.2 scoring function, simultaneous docking of multiple ligands, and a batch mode for docking a large number of ligands. Furthermore, we implemented Python bindings to facilitate scripting and the development of docking workflows. This work is an effort toward the unification of the features of the AutoDock4 and AutoDock Vina docking engines. The source code is available at <a href="https://github.com/ccsb-scripps/AutoDock-Vina" rel="noopener noreferrer" target="_blank">https://github.com/ccsb-scripps/AutoDock-Vina</a></pre>

Buffered EGFR signaling regulated by spitz to argos expression ratio is critical for patterning the Drosophila eye

The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays a critical role in regulating tissue patterning. Drosophila EGFR (DER) signaling achieves specificity through multiple ligands and feedback loops to finetune signaling spatiotemporally. The principal Drosophila EGF, cleaved Spitz, and the negative feedback molecule, Argos are diffusible and can act both in a cell autonomous and non-autonomous manner. The relative expression dose of Spitz and Argos early in development has been shown to be critical in patterning the Drosophila eye, but the exact identity of the cells expressing these genes in the larval eyedisc has been elusive. Using single molecule RNA Fluorescence in situ Hybridization (smFISH), we reveal an intriguing differential expression of spitz and argos in the Drosophila third instar eye imaginal disc indicative of directional DER signaling. By genetically tuning DER signaling, we show that rather than absolute levels of expression, the ratio of expression to be critical for determining the adult eye phenotype. Proper ommatidial patterning is robust to thresholds around a tightly maintained wildtype ratio, and breaks down beyond. This provides a powerful instance of developmental buffering.