Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease.

The NS3 serine protease enzyme of the hepatitis C virus (HCV) is essential for viral replication. Short peptides mimicking the N-terminal substrate cleavage products of the NS3 protease are known to act as weak inhibitors of the enzyme and have been used as templates for the design of peptidomimetic inhibitors. Automated solid-phase synthesis of a small library of compounds based on such a peptidomimetic scaffold has led to the identification of potent and highly selective inhibitors of the NS3 protease enzyme.     

(1,3‐Diphenyl‐1H‐Pyrazol‐4‐yl)‐Methylamine Analogues as Inhibitors of Dipeptidyl Peptidases

A number of pyrazole compounds reported in literatures elicit anti‐hyperglycemic effects. By modifying the side chain of the heterocyclic skeleton, a new chemical class of DPP‐IV inhibitors structurally derived from the (pyrazol‐4‐yl)‐methylamine scaffold have been discovered and evaluated the biological activities of these inhibitors against DPP‐IV, DPP8, DPP‐II and FAP. The SAR studies showed the (1,3‐diphenyl‐1H‐pyrazol‐4‐yl)‐methylamines with 2,4‐dichloro substituents at the 3‐phenyl ring selectively preferred as DPP‐IV inhibitors, whereas with difluoro substituents at the 3‐phenyl ring selectively preferred as DPP8 inhibitors. The binding mode of representative compound 15h at the active site of DPP‐IV was predicted by computer model. In additional, 15h exhibited the ability to significantly decrease the glucose excursion in mice.     

Peptides to peptidomimetics: towards the design and synthesis of bioavailable inhibitors of oligosaccharyl transferase

Oligosaccharyl transferase (OT) is the enzyme responsible for asparagine-linked glycosylation in the lumen of the endoplasmic reticulum, which is a subcellular compartment within eukaryotic cells. Inhibition of this enzyme within a cellular environment would provide a valuable investigative tool for glycobiology. Due to the limitations of peptides, none of the existing peptide-based inhibitors of OT demonstrate activity in cell-based enzyme assays. We report herein the design, synthesis and preliminary biological characterization of a family of peptidomimetics that inhibit OT with Ki values in the nanomolar range. The hexapeptide Bz-Dab-Ala-Thr-Val-Thr-Nph-NH2 (Ki = 69 nM) was used as the prototype for the design of bioavailable inhibitors. Several aminobenzoic acid spacer groups were evaluated as potential isosteres of the Val-Thr dipeptide unit and the peptidomimetic incorporating 3-aminobenzoic acid proved to inhibit OT with similar potency to the parent compound (Ki = 84 nM). Further modifications explored the effects of size, hydrophobicity and conformational rigidity on enzyme affinity. This study yielded a family of potent non-peptidic inhibitors that are viable candidates for the in vivo inhibition of OT.     

Design and Synthesis of a Novel Peptidomimetic Inhibitor of Caspase-3

Introduction Thecaspase(cysteinyl aspartateprotease)family representsaclassofintracellularproteases,playinga criticalroleinapoptoticcelldeathpathwaysandactiva tionofpro inflammatorycytokines[1].Theirenzymatic propertiesaregovernedbyanearlyabsolutespecific…     

3C-like蛋白酶抑制剂的构效关系、分子对接和分子动力学

3C-like蛋白酶是中东呼吸综合征冠状病毒（MERS-CoV）等其它冠状病毒的繁殖过程中极为重要的蛋白酶。它已成为人类在抗冠状病毒领域中的研究热点。本文基于计算生物学方法对与MERS-CoV同属的蝙蝠冠状病毒HKU4（HKU4-CoV）的43个肽类3C-like蛋白酶抑制剂分子,建立三维定量构效关系（3D-QSAR）模型。在基于配体叠合的基础上,发现比较分子相似性指数分析法（CoMSIA）中的四个场组合（位阻场、静电场、氢键供体场与氢键受体场）为最优的模型（Q²=0.522,R_ncv²=0.996,R_pre²=0.904;Q²：交叉验证相关系数,R_ncv²：非交叉验证相关系数,R_pre²：验证集分子的预测值相关系数）,并借助该模型通过分子对接（docking）与分子动力学（MD）方法阐明了配受体结合作用。实验结果表明：（1）基于最优的CoMSIA模型基础上的三维等势图形象地说明了分子基团的位阻作用、静电作用、氢键供体与氢键受体作用对分子生物活性的影响;（2）分子对接研究结果显示了疏水性以及结晶水、氨基酸His166和Glu169在配体和受体结合过程中产生重要作用;（3）分子动力学模拟进一步验证了分子对接模型的可靠性,并发现了两个新的关键氨基酸Ser24与Gln192,它们与配体产生了两个较强的氢键。此外,根据这些结果,一些新的具有潜在抑制活性的肽类化合物作为3C-like蛋白酶抑制剂被获得。以上结果能够帮助深入了解3C-like蛋白酶与肽类抑制剂的作用机理,并且能够为今后的抗MERS-CoV药物设计提供有价值的参考。     

Therapeutic Targeting of Oncogenic K‐Ras by a Covalent Catalytic Site Inhibitor

We report the synthesis of a GDP analogue, SML‐8‐73‐1, and a prodrug derivative, SML‐10‐70‐1, which are selective, direct‐acting covalent inhibitors of the K‐Ras G12C mutant relative to wild‐type Ras. Biochemical and biophysical measurements suggest that modification of K‐Ras with SML‐8‐73‐1 renders the protein in an inactive state. These first‐in‐class covalent K‐Ras inhibitors demonstrate that irreversible targeting of the K‐Ras guanine‐nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.     

Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases

In this paper, we present a parallel synthesis of several series of dipeptide diphenyl phosphonates that are known to be irreversible inhibitors of serine proteases. Polymer-assisted solution-phase synthesis (PASP) is used for the rapid and clean coupling between various alpha-aminoalkyl diphenyl phosphonate ester building blocks and commercially available or easily accessible amino acids. These compounds were used for the rapid profiling of dipeptidyl peptidase II (DPP II) and the closely related dipeptidyl peptidase IV (DPP IV). A highly selective DPP II inhibitor was identified, N-cyclopentylglycyl-NHCH(C(6)H(5))PO(OPh)(2) (9.35), that will be useful to discriminate between DPP II and DPP IV in biological systems in order to further elucidate the biological function of DPP II.     

Synthesis and optimization of peptidomimetics as HIV entry inhibitors against the receptor protein CD4 using STD NMR and ligand docking

We recently described the design and synthesis of a novel CD4 binding peptidomimetic as a potential HIV entry inhibitor with a KD value of approximately 35 microM and a high proteolytic stability [A. T. Neffe and B. Meyer, Angew. Chem., Int. Ed., 2004, 43, 2937-2940]. Based on saturation transfer difference (STD) NMR analyses and docking studies of peptidomimetics we now report the rational design, synthesis, and binding properties of 11 compounds with improved binding affinity. Surface plasmon resonance (SPR) resulted in a KD = 10 microM for the best peptidomimetic XI, whose binding affinity is confirmed by STD NMR (KD = 9 microM). The STD NMR determined binding epitope of the ligand indicates a very similar binding mode as that of the lead structure. The binding studies provide structure activity relationships and demonstrate the utility of this approach.     

Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies

The replacement of the amide bond in a peptide backbone is a promising strategy in peptidomimetic drug research. Over the various amide bond surrogates, the fluoroolefin moiety has been successfully developed as an effective mimic. Today, fluorine-containing compounds account for a large proportion of new active molecules in life sciences. The synthesis of fluoroolefin peptide mimics is not a trivial task and innovative approaches often need to be addressed, in particular for the stereocontrol of the double bond configuration and the chiral centres adjacent to the fluoroalkene. These fluorinated peptidomimetics have been synthesised and evaluated as metabolically stable and/or conformationally constrained analogs of enzyme inhibitors, and as tools for probing the function, structure, and binding process of receptors.     

Disclosing Interfaces of ZnO Nanocrystals Using Dynamic Nuclear Polarization: Sol‐Gel versus Organometallic Approach

The unambiguous characterization of the coordination chemistry of nanocrystal surfaces produced by wet‐chemical synthesis presently remains highly challenging. Here, zinc oxide nanocrystals (ZnO NCs) coated by monoanionic diphenyl phosphate (DPP) ligands were derived by a sol‐gel process and a one‐pot self‐supporting organometallic (OSSOM) procedure. Atomic‐scale characterization through dynamic nuclear polarization (DNP‐)enhanced solid‐state NMR (ssNMR) spectroscopy has notably enabled resolving their vastly different surface‐ligand interfaces. For the OSSOM‐derived NCs, DPP moieties form stable and strongly‐anchored μ₂‐ and μ₃‐bridging‐ligand pairs that are resistant to competitive ligand exchange. The sol‐gel‐derived NCs contain a wide variety of coordination modes of DPP ligands and a ligand exchange process takes place between DPP and glycerol molecules. This highlights the power of DNP‐enhanced ssNMR for detailed NC surface analysis and of the OSSOM approach for the preparation of ZnO NCs.     

The synthesis of azapeptidomimetic beta-lactam molecules as potential protease inhibitors

Synthetic methods for the construction of a novel peptidomimetic structure are reported. The structure incorporates a beta-lactam and an azapeptide in a peptide backbone with the intention of generating rationally designed substrate-based protease inhibitors. The beta-lactam is formed by subjecting serine or threonine-azapeptides to Mitsunobu reaction conditions. Importantly, the azapeptidomimetic beta-lactam structure permits extended binding inhibition and the synthetic methods to create tetrapeptidomimetic structures are described.     

Side reaction of significance in preparation of peptide- or peptidomimetic-based hydroxamate enzyme inhibitors

Peptidic and peptidomimetic hydroxamates are increasingly being developed as potential pharmaceutical agents in targeting metalloenzymes. For a number of practical considerations, the hydroxamate moiety is often introduced in the synthesis onto valuable advanced synthetic precursors. The approach entails activation of the carboxylate of the synthetic precursor by any number of methods for the preparation of the hydroxamate. We report herein that this widely used approach in preparation of an entire class of enzyme inhibitors is problematic as documented by the formation of an undesirable cyclization product (characterized in this report), which could at times be the exclusive outcome of the carboxylate activation process.     

Discovery of dipeptidyl peptidase Ⅳ(DPP4) inhibitors based on a novel indole scaffold

Dipeptidyl peptidase Ⅳ(DPP4) inhibitors are proven in the treatment of type 2 diabetes.We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9(DPP9)(200 fold).We further co-crystallized DPP4 with indole sulfonamide(compound 1) to confirm a proposed binding mode.Good metabolic stability of the indole compounds represents another positive attribute for further development.     

Synthesis and characterization of novel zwitterionic lipids with pH-responsive biophysical properties

We report the synthesis and biophysical characterization of a novel class of zwitterionic lipids (ZL) with head groups containing a 3° or 4° amine and carboxylate. ZL form stable liposomes that exhibit head group dependent, pH-responsive biophysical characteristics. These lipids may be suitable components for drug delivery applications due to their ease of synthesis and unique pH-dependent properties.     

Synthesis of novel HIV-1 protease inhibitors based on carbohydrate scaffolds

The synthesis of peptidomimetic inhibitors of HIV-1 protease based on 6-deoxy-6-amino-β-d-glucopyranoside and 6-deoxy-6-amino-β-d-mannopyranoside scaffolds has been achieved. The inhibitors had IC₅₀ values in the micromolar range. The results provide a platform for the development of more potent carbohydrate based inhibitors of HIV-1 and other aspartic proteases.     

Diketopyrrolopyrrole-containing quinoidal small molecules for high-performance, air-stable, and solution-processable n-channel organic field-effect transistors

We report the synthesis, characterization, and application of a novel series of diketopyrrolopyrrole (DPP)-containing quinoidal small molecules as highly efficient n-type organic semiconductors in thin film transistors (TFTs). The first two representatives of these species exhibit maximum electron mobility up to 0.55 cm(2) V(-1) s(-1) with current on/current off (I(on)/I(off)) values of 10(6) for 1 by vapor evaporation, and 0.35 cm(2) V(-1) s(-1) with I(on)/I(off) values of 10(5)-10(6) for 2 by solution process in air, which is the first demonstration of DPP-based small molecules offering only electron transport characteristics in TFT devices. The results indicate that incorporation of a DPP moiety to construct quinoidal architecture is an effective approach to enhance the charge-transport capability.     

A time-resolved fluorescence probe for dipeptidyl peptidase 4 and its application in inhibitor screening

The prevalence of type 2 diabetes is increasing dramatically throughout the world. Recently, dipeptidyl peptidase 4 (DPP4) was identified as a potential antidiabetes target. Many DPP4 inhibitors, such as sitagliptin and vildagliptin, have been developed and marketed, but superior therapeutic agents are still required. Therefore, we have developed new methodology for screening of DPP4 inhibitors. Absorption-based measurements with para-nitroaniline or fluorescence-based measurements with the coumarin derivative 7-amino-4-methylcoumarin are often used for the screening of protease inhibitors, including DPP4 inhibitors, but these strategies are not sufficiently sensitive because of interfering background absorption and fluorescence, thus giving rise to many false-positive and false-negative results. Therefore, we have designed and synthesised a novel DPP4 probe (Gly-Pro-BCD-Tb; Gly=glycine, Pro=proline, andBCD defines the backbone of the probe comprising an aniline derivative as on/off switch, a 7-amino-4-methyl-2(1H)-quinolinone (cs-124) as antenna moiety, and a diethylenetriamine-N,N,N',N',N'-pentaacetic acid (DTPA) as chelator moiety, Tb=terbium) for time-resolved fluorescence (TRF) measurements. TRF measurements with Gly-Pro-BCD-Tb showed high sensitivity and reliability in the inhibitory assay relative to Gly-Pro-MCA (MCA=4-methylcoumarin-7-amide), a conventional fluorescence probe for DPP4. Further, we employed our probe for high-throughput DPP4 inhibitor screening with 3841 randomly selected compounds and found that epibestatin, an epimer of bestatin (a well-known anticancer drug and general aminopeptidase inhibitor), showed dose-dependent DPP4 inhibitory activity. Interestingly, bestatin did not exhibit DPP4 inhibitory activity. We believe that this screening system will be useful for the discovery of DPP4 inhibitors with novel structural scaffolds.     

新型含硫肿瘤坏死因子类肽抑制剂的合成与活性

为了发展新型TNF类肽抑制剂, 考虑到酶活性中心含有Zn²⁺离子, 我们以通式1的骨架为基础, 设计并合成了一类含有硫原子的类肽化合物2, 其具有三肽的基本骨架, 羟胺的游离羟基和侧链上的硫原子均可与金属蛋白酶活性中心的Zn²⁺络合, 起抑制活性作用.     

Modeling ligand-receptor interaction for some MHC class II HLA-DR4 peptide mimetic inhibitors using several molecular docking and 3D QSAR techniques

The ligand-receptor interaction between some peptidomimetic inhibitors and a class II MHC peptide presenting molecule, the HLA-DR4 receptor, was modeled using some three-dimensional (3D) quantitative structure-activity relationship (QSAR) methods such as the Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Indices Analysis (CoMSIA), and a pharmacophore building method, the Catalyst program. The structures of these peptidomimetic inhibitors were generated theoretically, and the conformations used in the 3D QSAR studies were defined by docking them into the known structure of HLA-DR4 receptor through the GOLD, GLIDE Rigidly, GLIDE Flexible, and Xscore programs. Some of the parameters used in these docking programs were selected by docking an X-ray ligand into the receptor and comparing the root-means-square difference (RMSD) computed between the coordinates of the X-ray and docked structure. However, the goodness of a docking result for docking a series of peptidomimetic inhibitors into the HLA-DR4 receptor was judged by comparing the Spearman's rank correlation coefficient computed between each docking result and the activity data taken from the literature. The best CoMFA and CoMSIA models were constructed using the aligned structures of the best docking result. The CoMSIA was conducted in a stepwise manner to identify some important molecular features that were further employed in a pharmacophore building process by the Catalyst program. It was found that most inhibitors of the training set were accurately predicted by the best pharmacophore model, the Hypo1 hypothesis constructed. The deviation or conflict found between the actual and predicted activities of some inhibitors of both the training and the test sets were also investigated by mapping the Hypo1 hypothesis onto the corresponding structures of the inhibitors.     

Synthesis and characterization of optical and redox properties of bithiophene-functionalized diketopyrrolopyrrole chromophores

A series of six new 2,2'-bithiophene-functionalized diketopyrrolopyrrole (DPP) dyes 7a-f bearing different electron-donating and electron-withdrawing substituents at the terminal thiophene units was synthesized by palladium-catalyzed cross-coupling reactions. The to date unknown diiodinated DPP 2 and the corresponding boronic ester derivative 3 could be prepared in high yields, and these are shown to be versatile building blocks for the synthesis of DPP-based molecular materials by Negishi, Stille, and Suzuki coupling. The influence of the peripheral substituents on the optical and electrochemical properties of the present series of DPP dyes 7a-f were investigated by UV/vis and steady-state fluorescence spectroscopy and cyclic voltammetry, revealing an appreciable effect on the electronic nature of these dyes. The diamino-substituted DPP derivative 7e exhibits a strong absorption band reaching in the near-infrared (NIR) region, which is a highly desirable feature for application in organic photovoltaics.