Terminal Modification Research Articles

Molecular Engineering of membrane structure targeted photosensitizers for antitumor photodynamic therapy

Photodynamic therapy (PDT) has been used to cure special diseases or the diseases that localized at special sites in comparison with conventional therapy, due to its high spatiotemporal selectivity, non-invasion, low drug resistance. However, vast majority of photosensitizers (PSs) still suffer from several limitations including poor aqueous solubility and poor photostability. Here, we used two strategies, promoting the intramolecular charge transfer and terminal modification, to overcome these limitations and enhance therapeutic effects. Three membrane-structure targeted molecules, 3CN-Np, 3CN–OH, and 3CN-QA, were designed and synthesized, which exhibited high extinction coefficient, excellent photostability and reactive oxygen species (ROS) productive capacity. In cell imaging, the designing molecules would stain endoplasmic reticulum for 3CN-Np and 3CN–OH, and cell membrane for 3CN-QA, respectively. Afterwards, we used white light (25 mW/cm2) to irradiate the probe cultured cells for 20 min, the ratio of the dead and live cells was 3.0 for 3CN-Np, 3.5 for 3CN–OH, and 3.7 for 3CN-QA. Based on the high cell apoptosis in vitro under a white-light, 3CN–OH was selected to inhibited tumor growth in vivo, and the tumor volume was reduced to 45 % with non-toxicity to vitals. The study provided new sights in developing PSs with high water-solubility, photostability, and ROS generating ability in white-light mediating PDT system.

Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model uncovered by PANDORA-seq.

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

The restricted N-glycome of neurons is programmed during differentiation.

The protein glycome of individual cell types in the brain is unexplored, despite the critical function of these modifications in development and disease. In aggregate, the most abundant asparagine (N-) linked glycans in the adult brain are high mannose structures, and specifically Man 5 GlcNAc 2 (Man-5), which normally exits the ER for further processing in the Golgi. Mannose structures are uncommon in other organs and often overlooked or excluded in most studies. To understand cell-specific contributions to the unique brain N-glycome and its abundance of Man-5, we performed RNAseq and MALDI-MS TOF protein N-glycomics at several timepoints during differentiation of multiple cell types. To this end, homogeneous cultures of glutamatergic neurons, GABAergic neurons, and brain-specific endothelial cells were generated from monoclonal human inducible pluripotent stem cells (hiPSCs) through cellular reprogramming. Small molecule induction of stably integrated synthetic transcription units driving morphogen expression generated differentiated cells with distinct patterns mirroring intact tissue. Comparing uninduced hiPSCs for each cell type revealed identical transcriptomic and glycomic profiles before differentiation, with low quantities of Man-5. In differentiated glutamatergic and GABAergic neurons, the most abundant N-glycans became Man-5 and its immediate precursor Man-6, despite the presence of transcripts encoding enzymes for their subsequent modification. Differentiation to brain-specific endothelial cells showed an opposite effect, with the N-glycome displaying an abundance of complex N-glycans and terminal modifications of the late secretory pathway. These results confirm that the restricted N-glycome profile of brain is programmed into neuronal differentiation, with regulation independent of the transcriptome and under tight evolutionary constraint.

Terminal Chemical Modifications of crRNAs Enable Improvement in the Performance of CRISPR-Cas for Point-of-Care Nucleic Acid Detection.

CRISPR-Cas systems, harnessing their precise nucleic acid recognition via CRISPR RNA (crRNA), offer promise for the accurate testing of nucleic acids in the field. However, the inherent susceptibility of crRNA to degradation poses challenges for accurate detection in low-resource settings. Here, we utilized the chemically modified crRNA for the CRISPR-Cas-based assay (CM-CRISPR). We found that the extension and chemical modification to crRNA significantly enhanced the trans-cleavage activity of LbCas12a. The chemically modified crRNA was resistant to degradation, and CM-CRISPR showed superior detection capability in complex environments. CM-CRISPR could be combined with recombinase polymerase amplification (RPA) and applied in a droplet digital platform, enabling attomolar-level sensitivity. We also developed a portable and automated device for a digital CRISPR assay, which is amenable to point-of-care testing (POCT). The extraction-free procedure was integrated with this assay to streamline the workflow, and clinical samples were successfully detected. This work finds a simple and efficient way to improve the performance of CRISPR-Cas and develops a portable platform for POCT, representing a significant advance toward practical applications of CRISPR-based diagnostics.

Optimizing therapeutic efficacy of antifungal peptides via strategic terminal amino acid modification

IntroductionAntifungal peptides (AFPs) have the potential to treat antifungal-resistant infections; however, their structure–function relationship remains unknown, hindering their rapid development. Therefore, it is imperative to investigate and clarify the structure–function relationships of AFPs. ObjectivesThis study aimed to investigate the impact of end-tagging single hydrophobic amino acids and capping the N-terminus with glycine (Gly) on the antifungal activity of peptide W4. MethodsThe antifungal efficacy of the engineered peptides was initially assessed by determining the minimum inhibitory concentration (MIC) /minimal fungicidal concentration (MFC), killing kinetics, and drug resistance induction, in addition to evaluating the biocompatibility and stability. Subsequently, the antifungal mechanism was investigated using fluorescence labeling, electron microscopy, reactive oxygen species (ROS) detection, and measurement of mitochondrial membrane potential and apoptosis. The impact of the engineered peptides on Candida albicans (C. albicans) biofilm and their potential application in the scratch keratomycosis model were investigated. ResultsThe antifungal activity of W4 was significantly enhanced by capping Gly at the N-terminus, resulting in a decrease in average activity from 11.86 μM to 6.25 μM (GW4) and an increase in TI values by 1.9-fold (TIGW4 = 40.99). Mechanistically, GW4 exerted its antifungal effect by disrupting the cellular membrane structure in C. albicans, forming pores and subsequent leakage of intracellular contents. Concurrently, it facilitated intracellular ROS accumulation while decreasing the mitochondrial membrane potential. Additionally, GW4 demonstrated an excellent ability to inhibit and eliminate biofilms of C. albicans. Notably, GW4 demonstrated significant therapeutic potential in a C. albicans-associated keratitis model. ConclusionCapping Gly at the N-terminus increased residue length while significantly enhancing the helical propensity of W4, thereby augmenting its antifungal activity. Our exploratory study demonstrated the potential strategies and avenues for optimizing the structure–function relationships of AFPs and developing highly effective antifungal drugs.

Tailoring surface terminals of Ti3C2Tx MXene microgels via interlayer domain-confined polyphosphate ammonium for flexible supercapacitor applications

The MXene material shows potential for flexible energy storage devices due to its high pseudocapacitance and mechanical flexibility. However, MXene nanosheet self-stacking and –F terminal functional groups can hinder active site and ion dynamics, thus affecting the energy storage performance. Herein, we present an interlayer domain-confined strategy that involves the introduction and crosslinking of ammonium polyphosphate (APP) confined to the interlayer of Ti3C2Tx MXene sheets, which induces gelation of the MXene to form a 3D network structure and enlarge their interlayer spacing. And then the cross-linked APP is converted into nitrogen and phosphorus terminals on Ti3C2Tx MXene via thermal treatment. The nitrogen terminals in the form of the pyrrole nitrogen and pyridine nitrogen, and phosphorus terminals of P–O bonds enhance the activity of the redox reaction and the dynamics of the ions, resulting in the boosted energy storage capacity of MXene. The density functional theory (DFT) calculations reveal that nitrogen-phosphorus co-doping modulates the surface electronic states of MXene and contributes to the increase of the electrical conductivity of Ti3C2Tx MXene. As a supercapacitor electrode, Ti3C2Tx MXene with N/P terminals exhibits a higher specific capacitance of 597.8 F/g (1777F cm−3) than the raw Ti3C2Tx MXene (384 F/g). In addition, the quasi-solid state flexible symmetric supercapacitor assembled by Ti3C2Tx MXene with N/P terminals can achieve an energy density of 12.5 Wh kg−1 at a power density of 250 W kg−1. Therefore, this work provides a new strategy for terminal modification of MXene and high-performance MXene supercapacitors.

Synthesis and Characterization of Multifunctional Symmetrical Squaraine Dyes for Molecular Photovoltaics by Terminal Alkyl Chain Modifications

Novel far-red sensitive symmetric squaraine (SQ) dyes with terminal alkyl chain modifications were designed, synthesized, and characterized, aiming towards imparting multifunctionalities such as photosensitization, dye aggregation prevention, and source of electrolyte components. The dye sensitizer SQ-80 with alkyl chain terminal modifications consisting of 1-methylimidazolium iodide was designed and synthesized as a new dye sensitizer for DSSCs based on symmetric SQ-4 without any terminal modification used as reference. Upon adsorption on the mesoporous TiO2 surface, SQ-80 demonstrated reduced dye aggregation and stronger binding to the TiO2 surface, leading to enhanced durability of DSSCs. Apart from the most common photosensitization behavior, the newly designed dye demonstrated multifunctionalities such as aggregation prevention and electrolyte functionality, utilizing iodine-based redox electrolytes in the presence and absence of I2 and LiI additives. In the absence of LiI and I2, a mixture of SQ-77 with alkyl chain terminal modifications consisting of iodide and SQ-80 demonstrated a photoconversion efficiency of 1.54% under simulated solar irradiation, which was about six times higher compared with the reference dye SQ-4 (0.24%) (having no alkyl chain terminal modification).

Spliceosomal snRNAs, the Essential Players in pre-mRNA Processing in Eukaryotic Nucleus: From Biogenesis to Functions and Spatiotemporal Characteristics.

Spliceosomal small nuclear RNAs (snRNAs) are a fundamental class of non-coding small RNAs abundant in the nucleoplasm of eukaryotic cells, playing a crucial role in splicing precursor messenger RNAs (pre-mRNAs). They are transcribed by DNA-dependent RNA polymerase II (Pol II) or III (Pol III), and undergo subsequent processing and 3' end cleavage to become mature snRNAs. Numerous protein factors are involved in the transcription initiation, elongation, termination, splicing, cellular localization, and terminal modification processes of snRNAs. The transcription and processing of snRNAs are regulated spatiotemporally by various mechanisms, and the homeostatic balance of snRNAs within cells is of great significance for the growth and development of organisms. snRNAs assemble with specific accessory proteins to form small nuclear ribonucleoprotein particles (snRNPs) that are the basal components of spliceosomes responsible for pre-mRNA maturation. This article provides an overview of the biological functions, biosynthesis, terminal structure, and tissue-specific regulation of snRNAs.

Small Ionic‐Liquid‐Based Molecule Drives Strong Adhesives

AbstractNature has inspired scientists to fabricate adhesive materials for applications in many burgeoning areas. However, it is still a significant challenge to develop small‐molecule adhesives with high‐strength, low‐temperature and recyclable properties, although these merits are of great interest in various aspects. Herein, we report a series of strong adhesives based on low‐molecular‐weight molecular solids driven by the terminal modification of ionic liquids (ILs) and subsequent supramolecular self‐assembly. The emergence of high strength and liquid‐to‐solid transitions for these supramolecular aggregates relies on modifying IL with a high melting point motif and enriching the types of noncovalent interactions in the original ILs. Using this strategy, we demonstrate that our IL‐based molecular solids can efficiently obtain a high adhesion strength (up to 8.95 MPa). Importantly, we elucidate the mechanism underlying the reversible and strong adhesion enabled by monomer‐to‐polymer transitions. These fundamental findings provide guidance for the design of high‐performance supramolecular adhesive materials.

Small Ionic-Liquid-Based Molecule Drives Strong Adhesives.

Nature has inspired scientists to fabricate adhesive materials for applications in many burgeoning areas. However, it is still a significant challenge to develop small-molecule adhesives with high-strength, low-temperature and recyclable properties, although these merits are of great interest in various aspects. Herein, we report a series of strong adhesives based on low-molecular-weight molecular solids driven by the terminal modification of ionic liquids (ILs) and subsequent supramolecular self-assembly. The emergence of high strength and liquid-to-solid transitions for these supramolecular aggregates relies on modifying IL with a high melting point motif and enriching the types of noncovalent interactions in the original ILs. Using this strategy, we demonstrate that our IL-based molecular solids can efficiently obtain a high adhesion strength (up to 8.95 MPa). Importantly, we elucidate the mechanism underlying the reversible and strong adhesion enabled by monomer-to-polymer transitions. These fundamental findings provide guidance for the design of high-performance supramolecular adhesive materials.

EnDL-HemoLyt: Ensemble Deep Learning-based Tool for Identifying Therapeutic Peptides with Low Hemolytic Activity.

Low hemolytic therapeutic peptides have gained an edge over small molecule-based medicines. However, finding low hemolytic peptides in laboratory is time-consuming, costly and necessitates the use of mammalian red blood cells. Therefore, wet-lab researchers often perform in-silico prediction to select low hemolytic peptides before proceeding with in-vitro testing. The in-silico tools available for this purpose have following limitations: (i) They do not provide predictions for peptides having N/C terminal modifications. (ii) Data is food for AI; however, datasets used to create existing tools do not contain peptide data generated over past eight years. (iii) Performance of available tools is also low. Therefore, a novel framework has been proposed in current work. Proposed framework utilizes recent dataset and uses ensemble learning technique to combine the decisions produced by bidirectional long short-term memory, bidirectional temporal convolutional network, and 1-dimensional convolutional neural network deep learning algorithms. Deep learning algorithms are capable of extracting features themselves from data. However, instead of relying solely on deep learning-based features (DLF), handcrafted features (HCF) were also provided so that deep learning algorithms can learn features that are missing from HCF, and a better feature vector can be constructed by concatenating HCF and DLF. Additionally, ablation studies were carried out to understand the roles of an ensemble algorithm, HCF, and DLF in the proposed framework. Ablation studies found that the ensemble algorithm, HCF and DLF are crucial components of proposed framework, and there is a decrease in performance on eliminating any of them. Mean value of performance metrics, namely Acc, Sn, Pr, Fs, Sp, Ba, and Mcc obtained by proposed framework for test data is ≈ 87, 85, 86, 86, 88, 87, and 73, respectively. To aid scientific community, model developed from proposed framework has been deployed as a web server at https://endl-hemolyt.anvil.app/.

Regulating nitrogen/sulfur terminals on 3D porous Ti3C2 MXene with enhanced reaction kinetics toward high-performance alkali metal ion storage

In this paper, we have developed a simple and efficient sulfur-amine chemistry strategy to prepare a three-dimensional (3D) porous Ti3C2Tx composite with large amounts of N and S terminal groups. The well-designed 3D macroporous architecture presents enlarged interlayer spacing, large specific surface area, and unique porous structure, which successfully solves the re-stacking issue of MXene during storage and electrode fabrication. It is the amount of concentrated hydrochloric acid added to the S-EDA (ethylenediamine)/MXene colloidal suspension that is critical to the formation of 3D morphology. In addition, N and S terminals on MXene could improve the adsorption ability of K+. Owing to the synergistic effect of the structure design and terminal modification, the N, S codoped three-dimensional porous Ti3C2Tx (3D-NSPM) material shows a high surface capacitive contribution and rapid diffusion kinetics for K+ and Na+. As a result, the as-prepared 3D-NSPM delivers high reversible capacity (237 and 273 mAh g−1 at 0.1 A g−1 for PIBs and SIBs, respectively), superb cycling stability (84.9% capacity retention after 10,000 cycles at 1 A g−1 in PIBs and 74.0% capacity retention after 2200 cycles at 1 A g−1 in SIBs), and excellent rate capability (111 and 196 mAh g−1 at 5 A g−1 for PIBs and SIBs, respectively), which are superior to other MXene-based anodes for PIBs and SIBs. Moreover, the described strategy provides a new insight for constructing the 3D porous structure from 2D building blocks beyond MXene.

NAP-seq reveals multiple classes of structured noncoding RNAs with regulatory functions

Up to 80% of the human genome produces “dark matter” RNAs, most of which are noncapped RNAs (napRNAs) that frequently act as noncoding RNAs (ncRNAs) to modulate gene expression. Here, by developing a method, NAP-seq, to globally profile the full-length sequences of napRNAs with various terminal modifications at single-nucleotide resolution, we reveal diverse classes of structured ncRNAs. We discover stably expressed linear intron RNAs (sliRNAs), a class of snoRNA-intron RNAs (snotrons), a class of RNAs embedded in miRNA spacers (misRNAs) and thousands of previously uncharacterized structured napRNAs in humans and mice. These napRNAs undergo dynamic changes in response to various stimuli and differentiation stages. Importantly, we show that a structured napRNA regulates myoblast differentiation and a napRNA DINAP interacts with dyskerin pseudouridine synthase 1 (DKC1) to promote cell proliferation by maintaining DKC1 protein stability. Our approach establishes a paradigm for discovering various classes of ncRNAs with regulatory functions.

Theoretical investigation of substituted end groups in thiophene‐phenyl‐thiophene (TPT) derivatives for high efficiency organic solar cells

AbstractThe field of organic solar cells has witnessed notable advancements in the past few years, mostly due to the development of novel materials for the active layer. The current investigations reveal the potential of nine previously unexplored molecules (TP1–TP9) designed by end group modification of TPT4F molecule. These molecules were investigated at MPW1PW91/6‐31G (d, p) with DFT and TD‐DFT approach to study the various photovoltaic and geometrical parameters. The results obtained through computations indicated improvement in the investigated parameters. The terminal group modification shifted the absorption maximum towards longer wavelength in the UV‐visible region. Highly conjugated modified acceptors reduced the band gap. The lower excitation energies increased the rate of charge transfer. The designed molecules showed improved excited state lifetime in comparison to the reference. The open circuit voltage was determined using the PTB7 polymer, which exhibited a noticeable improvement, especially in TP1 (1.70 eV), TP3 (1.75 eV), TP4 (1.68 eV), TP6 (1.85 eV), and TP7 (1.75 eV) when compared with reference (1.59 eV). Moreover, charge transfer investigations of designed molecules with PTB7 complex were performed by analyzing the concentration of charge transfer over molecular orbitals, that is, HOMO to LUMO. All of the preceding investigations targeted to achieve high‐efficiency organic cells reveal that the altered molecules can be considered effective candidates to tackle future energy problems.

Designing Thieno[3,4-c]pyrrole-4,6-dione Core-Based, A2-D-A1-D-A2-Type Acceptor Molecules for Promising Photovoltaic Parameters in Organic Photovoltaic Cells.

Nonfullerene-based organic solar cells can be utilized as favorable photovoltaic and optoelectronic devices due to their enhanced life span and efficiency. In this research, seven new molecules were designed to improve the working efficiency of organic solar cells by utilizing a terminal acceptor modification approach. The perceived A2-D-A1-D-A2 configuration-based molecules possess a lower band gap ranging from 1.95 to 2.21 eV compared to the pre-existing reference molecule (RW), which has a band gap of 2.23 eV. The modified molecules also exhibit higher λmax values ranging from 672 to 768 nm in the gaseous and 715-839 nm in solvent phases, respectively, as compared to the (RW) molecule, which has λmax values at 673 and 719 nm in gas and chloroform medium, respectively. The ground state geometries, molecular planarity parameter, and span of deviation from the plane were analyzed to study the planarity of all of the molecules. The natural transition orbitals, the density of state, molecular electrostatic potential, noncovalent interactions, frontier molecular orbitals, and transition density matrix analysis of all studied molecules were executed to validate the optoelectronic properties of these molecules. Improved charge mobilities and dipole moments were observed, as newly designed molecules possessed lower internal reorganization energies. The open circuit voltage (Voc) of W4, W5, W6, and W7 among newly designed molecules was improved as compared to the reference molecule. These results elaborate on the superiority of these novel-designed molecules over the pre-existing (RW) molecule as potential blocks for better organic solar cell applications.

Terminal modifications independent cell-free RNA sequencing enables sensitive early cancer detection and classification

Cell-free RNAs (cfRNAs) offer an opportunity to detect diseases from a transcriptomic perspective, however, existing techniques have fallen short in generating a comprehensive cell-free transcriptome profile. We develop a sensitive library preparation method that is robust down to 100 µl input plasma to analyze cfRNAs independent of their 5’-end modifications. We show that it outperforms adapter ligation-based method in detecting a greater number of cfRNA species. We perform transcriptome-wide characterizations in 165 lung cancer, 30 breast cancer, 37 colorectal cancer, 55 gastric cancer, 15 liver cancer, and 133 cancer-free participants and demonstrate its ability to identify transcriptomic changes occurring in early-stage tumors. We also leverage machine learning analyses on the differentially expressed cfRNA signatures and reveal their robust performance in cancer detection and classification. Our work sets the stage for in-depth study of the cfRNA repertoire and highlights the value of cfRNAs as cancer biomarkers in clinical applications.

Medium-sized peptides from microbial sources with potential for antibacterial drug development.

Covering: 1993 to the end of 2022As the rapid development of antibiotic resistance shrinks the number of clinically available antibiotics, there is an urgent need for novel options to fill the existing antibiotic pipeline. In recent years, antimicrobial peptides have attracted increased interest due to their impressive broad-spectrum antimicrobial activity and low probability of antibiotic resistance. However, macromolecular antimicrobial peptides of plant and animal origin face obstacles in antibiotic development because of their extremely short elimination half-life and poor chemical stability. Herein, we focus on medium-sized antibacterial peptides (MAPs) of microbial origin with molecular weights below 2000 Da. The low molecular weight is not sufficient to form complex protein conformations and is also associated to a better chemical stability and easier modifications. Microbially-produced peptides are often composed of a variety of non-protein amino acids and terminal modifications, which contribute to improving the elimination half-life of compounds. Therefore, MAPs have great potential for drug discovery and are likely to become key players in the development of next-generation antibiotics. In this review, we provide a detailed exploration of the modes of action demonstrated by 45 MAPs and offer a concise summary of the structure-activity relationships observed in these MAPs.

An electrochemical method based on CRISPR-Cas12a and enzymatic reaction for the highly sensitive detection of tumor marker MUC1 mucin.

Anti-cancer therapy is crucial in cancer prevention and anti-cancer, and thus, highly sensitive methods for detecting cancer biomarkers are essential for cancer early diagnosis. Herein, an electrochemical aptamer biosensor based on the CRISPR-Cas12a system was constructed for the detection of cancer tumor biomarker MUC1 mucin. The sensitivity was significantly prompted by enzyme-catalyzed signal amplification, and the selectivity was improved by the dual recognition of the aptamer to MUC1 and crRNA-Cas12a system to the aptamer. Glucose oxidase (GOD) was loaded on the surface of magnetic Fe3O4@Au (MGNP) via probe single-stranded DNA (pDNA) with the terminal modification of mercapto (-SH) to form GOD-pDNA/MGNP. The corresponding aptamer of MUC1 (MUC1 Apt) binds to its complementary ssDNA (cDNA) to form the activator Apt/cDNA, which is specifically recognized by crRNA-Cas12a and excites the trans-cleavage function of Cas12a, thus in turn trans-cleaves pDNA and detaches GOD from the magnetic particles. The magnetic beads were separated and transferred into a glucose solution, and the oxidation current of H2O2 produced by the catalytic reaction of GOD was measured on a Pt-modified magnetically-controlled glassy carbon electrode, resulting in an indirect determination of MUC1. The current change was linear with the logarithm of MUC1 concentration in the range from 1.0 × 10-17 g mL-1 to 1.0 × 10-10 g mL-1. The detection limit was as low as 7.01 × 10-18 g mL-1. The method was applied for the detection of MUC1 in medical samples.

Big peptide drugs in a small molecule world.

A quarter of a century ago, designer peptide drugs finally broke through the glass ceiling. Despite the resistance by big pharma, biotechnology companies managed to develop injectable peptide-based drugs, first against orphan or other small volume diseases, and later for conditions affecting large patient populations such as type 2 diabetes. Even their lack of gastrointestinal absorption could be utilized to enable successful oral dosing against chronic constipation. The preference of peptide therapeutics over small molecule competitors against identical medical conditions can be achieved by careful target selection, intrachain and terminal amino acid modifications, appropriate conjugation to stability enhancers and chemical space expansion, innovative delivery and administration techniques and patient-focused marketing strategies. Unfortunately, however, pharmacoeconomical considerations, including the strength of big pharma to develop competing small molecule drugs, have somewhat limited the success of otherwise smart peptide-based therapeutics. Yet, with increasing improvement in peptide drug modification and formulation, these are continuing to gain significant, and growing, acceptance as desirable alternatives to small molecule compounds.

Multiscale Simulations to Discover Self-Assembled Oligopeptides: A Benchmarking Study.

Peptide self-assembly is critical for biomedical and material discovery and production. While it is costly to experimentally test every possible peptide design, computational assessment provides an affordable solution to evaluate many designs and prioritize synthesis and characterization. Following a theoretical investigation, we present a systematic analysis of all-atom and coarse-grained simulations to predict peptide self-assembly. Benchmarking studies of two model dipeptides allow us to assess the impacts of intrinsic properties (such as amino acids and terminal modifications) and external environment (such as salinity) on the simulated aggregation. Further examination of 20 oligopeptides containing two to five amino acids shows good agreement among our theory, simulations, and prior experimental observations. The success rate of our prediction is 90%. Therefore, our theory, simulation, and analysis can be useful to identify peptide designs that can self-assemble and predict the potential nanostructures. These findings lay the ground for future virtual screening of peptide-assembled nanostructures and computer-aided biologics design.