Chemical protein synthesis-assisted high-throughput screening strategies (e.g., mirror-image phage display, mirror-image one-bead one-compound approaches) for d-peptide ligands were reviewed.
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d-peptides are recognized as a new class of synthetic chemical drugs and they possess many interesting advantages such as high enzymatic stability, improved oral bioavailability, as well as high binding affinity and specificity. Recently, d-peptide drugs have been attracting increasing attention in both academic and industrial researches over recent years. One d-peptide etelcalcetide has even entered the market that targets the calcium (Ca2+)-sensing receptor (CaSR) to fight secondary hyperparathyroidism. Effective discovery and optimization of d-peptide ligands that can bind to various disease-related targets with high specificity and potency is of great importance for the development of d-peptide drugs. This review surveys the recent method development in this area especially the chemical protein synthesis-assisted high-throughput screening strategies for d-peptide ligands and their application in drug discovery.
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•The hydrophobic part adsorbed on the surface of the poorly soluble drug.•The hydrophilic part exposed to the aqueous medium.•Self-assemble to form an interfacial phospholipid ...film.•Improve dissolution rate, storage stability and bioavailability of Ginkgolides.
The purpose of this study was to investigate the effects of soybean phospholipid, as a steric stabilizer, on improving dissolution rate, storage stability and bioavailability of ginkgolides. The ginkgolides coarse powder, hydroxypropyl methylcellulose (HPMC), soybean phospholipid and sodium dodecyl sulfate (SDS) were mixed and wet-milled to prepare nanosuspension S1. Nanosuspension S2 was obtained by the same technique except adding the soybean phospholipid. Results of particle size showed that particle size (D50) of S1 significantly decreased from 44.25 μm to 0.373 μm. Results of differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and transmission electron microscope (TEM) showed that ginkgolides in nanosuspension still maintained its crystallinity, and the nanoparticles were all nearly circular and uniformly dispersed. Then, pellets F1 and F2 were prepared by layering S1 and S2 onto the microcrystalline cellulose (MCC) spheres, respectively. The dissolution rate of ginkgolide A (GA) and ginkgolide B (GB) in F1 was 98.3% and 97.7% in 30 min, respectively. It was much higher than F2 (89.0% and 86.5%) and coarse powder of ginkgolides (22.3% and 24.6%). According to the results of stability test, the storage stability of F1 was improved compared with F2. In addition, compared with coarse powder of ginkgolides, the relative bioavailability of GA and GB in F1 were up to (221.84 ± 106.67) % and (437.45 ± 336.43) %, respectively. The above results demonstrated that soybean phospholipid added to the nanosuspension played an important role in improving drug dissolution rate, storage stability and in vivo bioavailability: (1) The amphiphilic soybean phospholipid interacted with the drug, with the hydrophobic part adsorbed on the surface of the poorly soluble drug and the hydrophilic part exposed to the aqueous medium. This increases the wettability of the nanoparticles, which ensure a good redispersibility of the drug particles. (2) It could self-assemble to form an interfacial phospholipid film by surrounding the individual nanoparticles, which can produce enough steric hindrance to prevent nanoparticles from aggregation and ensure a rapid dissolution rate. (3) Soybean phospholipid and its hydrolysate formed strong micellar solubilizing vehicles with bile salts in vivo, stimulated the absorption process of ginkgolides. Thus, soybean phospholipid was a promising steric stabilizer in nanosuspension drug delivery system.
This study presents a robustness analysis of shield tunnels in non-uniformly settled strata based on the fuzzy point estimate method (FPEM) and geotechnical structural robustness analysis methods. ...The uncertainties of key geotechnical parameters and loads were characterized using the fuzzy sets and the influence ofdifferentfuzzy membership functions andboundary values on the robustness index of shield tunnel was investigated. The structural design of the shield tunnel cross-section in non-uniformly settled strata were optimized by considering the reliability and robustness indices of the shield tunnel under the ultimate limit states, serviceability limit states, and economic costs. The results indicate that compared with the traditional Monte Carlo simulations, the FPEM is computationally efficient with favorable accuracy, and is suitable for the robustness analysis of shield tunnels. Increase of the segment thickness, reinforcement ratio and diameter of the joint bolts can efficiently improve the design robustness of the shield tunnel. Besides, the boundary values and distribution characteristics of the membership function of the random variables in the FPEM have significant effects on the errors of the calculation results.
A practical strategy for the total stepwise solid-phase synthesis of peptide-oligonucleotide conjugates was developed. In this strategy, the Boc/
Bu protecting groups are utilized for the side chains ...of Trp, His, Arg, Asp, and Glu, and is deprotected in borate buffer at 90 °C to avoid depurination of the oligonucleotide caused by strong acid treatment. The advantage of this strategy is that the abovementioned amino acids are readily available in the market and the side reaction of deguanidination of the Arg residue can be avoided. This side-chain Boc/
Bu protection strategy will expand the applicability of total stepwise synthesis in the preparation of peptide-oligonucleotide conjugates.
As ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) are widely distributed in the central and peripheral nervous systems and are associated with the pathogenesis of various ...degenerative neurological diseases. Here, we report the results of phage display-based de novo screening of an 11-residue linear peptide (named LKP1794) that targets the α7 nAChR, which is among the most abundant nAChR subtypes in the brain. Moreover, two d-peptides were generated through mirror image and/or primary sequence inverso isomerization (termed DRKP1794 and DKP1794) and displayed improved inhibitory effects (IC50 = 0.86 and 0.35 μM, respectively) on α7 nAChR compared with the parent l-peptide LKP1794 (IC50 = 2.48 μM), which markedly enhanced serum stability. A peptide-based fluorescence probe was developed using proteolytically resistant DKP1794 to specifically image the α7 nAChR in living cells. This work provides a new peptide tool to achieve inhibitory modulation and specifically image the α7 nAChR.
In order to enhance the lipophilicity and thus oral bioavailability of icariin (ICA) and icariside II (ICA II) of total flavonoids of epimedium (TFE), a total flavonoids of epimedium–phospholipid ...complex (TFE‐PLC) is prepared by wet media milling. The stabilizers Aerosi and SDS are used to formulate TFE‐PLC nanosuspensions (TFE‐PLC–Ns) to improve the dispersion of TFE–PLC. FTIR and DSC data confirms the formation of TFE‐PLC. The oil solubility of ICA and ICA II in the complex in octanol is improved nearly four times over that in TFE. The logP of ICA in TFE‐PLC is significantly increased with a value from 1.61 to 2.02 at pH 4.5, and ICA II, from 3.24 to 4.77. The mean diameter of the TFE‐PLC‐Ns is reduced from 6.166 to 0.424 μm, and its dissolution is improved over TFE. In the in vivo evaluation, TFE‐PLC‐Ns exhibits a considerable enhancement with larger AUC0–t and shorter Tmax than TFE and TFE‐PLC. The relative bioavailability of ICA in TFE‐PLC and TFE‐PLC‐Ns are 181.75 and 249.05%, respectively, and for ICA II are 401.63 and 684.70%, respectively. Therefore, it suggests that TFE‐PLC‐Ns has possibilities in enhancing oral bioavailability of TFE, which may be due to its improved lipophilicity and wettability.
Practical Applications: The oral bioavailability of ICA and ICA II in TFE are very low due to their poor lipophilicity and cell permeability. Here, TFE‐PLC‐Ns is proposed, which is prepared by wet media milling for improving lipophilic properties and oral bioavailability. In addition, some proofs of TFE‐PLC are investigated in detail, and TFE‐PLC‐Ns significantly increased the oral bioavailability of ICA and ICA II in TFE. Therefore, the authors recommend a potential drug vehicle of TFE‐PLC‐Ns for oral administration of ICA and ICA II, and a novel method of phospholipid complex preparation for industrial manufacture.
In this article, the total flavonoids of epimedium–phospholipid complex (TFE‐PLC) is prepared to enhance the lipophilicity of icariin (ICA) and icariside II (ICA II) in TFE. Aerosi and SDS are used to formulate TFE‐PLC nanosuspensions (TFE‐PLC‐Ns) to improve the dispersion of TFE‐PLC. And finally, TFE‐PLC‐Ns exhibits enhanced oral bioavailability of ICA and ICA II compared with them in TFE and TFE‐PLC.
In this article, the total flavonoids of epimedium–phospholipid complex (TFE‐PLC) is prepared to enhance the lipophilicity of icariin (ICA) and icariside II (ICA II) in TFE. Aerosi and SDS are used to formulate TFE‐PLC nanosuspensions (TFE‐PLC‐Ns) to improve the dispersion of TFE‐PLC. And finally, TFE‐PLC‐Ns exhibits enhanced oral bioavailability of ICA and ICA II compared with them in TFE and TFE‐PLC.
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Molecular interactions between the hydrophobic compound AD-1 and phospholipid DSPC were investigated.The monolayer composition and intermolecular distance had a marked effect on ...drug/lipid interfacial interactions.The interfacial stabilization of AD-1/DSPC was due to the hydrophobic interaction and the steric conformation recognition.Interfacial behaviors of mixed monolayers could reflected the loading efficiency of the corresponding drug delivery systems.
In this study, molecular interactions between the anti-cancer agent 20(R)-25-methoxyl-dammarane-3β, 12β, 20-triol (AD-1) and phospholipid 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) were investigated using the Langmuir film balance technique. The characteristics of binary Langmuir monolayers consisting of DSPC and AD-1 were conducted on the basis of the surface pressure⿿area per molecule (Ͽ⿿A) isotherms. It was found that the drug was able to become efficiently inserted into preformed DSPC monolayers, indicating a preferential interaction between AD-1 and DSPC. For the examined lateral pressure at 20mN/m, the largest negative values of οGex were found for the AD-1/DSPC monolayer, which should be the most stable. Based on the calculated values of οGex, we found that the AD-1/DSPC systems exhibited the best mixed characteristics when the molar fraction of the AD-1 was 0.8; at that relative concentration, the AD-1 molecules can mix better and interact with the phospholipid molecules. In addition, the drug-DSPC binary supramolecular structure was also deposited on the mica plates as shown by atomic force microscopy (AFM). Finally, molecular docking calculations explained satisfactorily that, based on the conformations interactions (conformation recognition), even at an AD-1/DSPC molar ratio as high as 8:2, the interfacial stabilization of the AD-1/DSPC system was fairly strong due to hydrophobic interactions. A higher loading capacity of DSPC might be possible, as it is associated with a more flexible geometrical environment, which allows these supramolecular structures to accept larger increases in drug loading upon steric binding.
Heating the human body to maintain a relatively constant temperature is pivotal for various human functions. However, most of the current heating strategies are energy-consuming and energy-wasting ...and cannot cope with the complex and changing environment. Developing materials and systems that can heat the human body precisely via an efficient energy-saving approach no matter indoors/outdoors, day/night, and sunny/cloudy is highly anticipated for mitigating the growing energy crisis and global warming but is still a great challenge. Here, we demonstrate the low mid-infrared radiative (mid-IR) emissivity characteristic of Ti3C2T x MXene and then apply it for energy-free passive radiative heating (PRH) on the human body. Our strategy is realized by simply decorating the cheap nanoporous polyethylene (nanoPE) textile with MXene. Impressively, the as-obtained 12 μm thick MXene/nanoPE textile shows a low mid-IR emissivity of 0.176 at 7–14 μm and outstanding indoor PRH performance on the human body, which enhances by 4.9 °C compared with that of traditional 576 μm thick cotton textile. Meanwhile, the MXene/nanoPE textile exhibits excellent active outdoor solar heating and indoor/outdoor Joule heating capability. The three heating modes integrated in this wearable MXene/nanoPE heating system can be switched easily or combined arbitrarily, making this thin heating system able to heat the human body precisely in various scenarios like indoors/outdoors, day/night, and sunny/cloudy, providing multiple promising and energy-saving solutions for future all-day personal precision thermal management.
Thermal camouflage has attracted increasing attention owing to the rapid development of infrared (IR) surveillance technologies. Various materials and systems have been developed to date, but the ...realization of high‐temperature thermal camouflage using ultrathin film/coating remains a great challenge; this is of great significance, especially for IR stealth in military equipment. This work demonstrates a series of ultrathin Ti3C2Tx MXene films (as low as 1 µm) with superior high‐temperature indoor/outdoor thermal camouflage performance: wide camouflage temperature range (from below −10 °C to over 500 °C), large reduction in radiation temperature (exceeding 300 °C for objects with temperatures over 500 °C), long‐term high‐temperature or fire stability, multifunctionality including disguised Joule heating capability, and high electromagnetic interference shielding efficiency. The superior high‐temperature thermal camouflage performance of the ultrathin MXene film is attributed to its low mid‐IR emissivity (0.19), which is comparable to that of stainless steel but far below that of other 2D nanomaterials, such as graphene. The multifunctional ultrathin MXene films prepared through simple vacuum‐assisted filtration provide a feasible method for efficient high‐temperature thermal camouflage using ultrathin films, demonstrating the great promise of MXene materials for thermal camouflage, IR stealth, counter‐surveillance, and security protection.
This work provides a facile strategy for efficient high‐temperature thermal camouflage using ultrathin MXene films/coatings; the performance of the MXene films/coatings is almost comparable to that of stainless steel and superior to that of other 2D nanomaterials as well as other reported film‐/coating‐based thermal camouflage materials/systems. The results of this work demonstrate the great promise of MXene materials for thermal camouflage, infrared stealth, counter‐surveillance, and security protection.
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