抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Molecular self-assembly is the spontaneous association of molecules under equilibrium conditions into stable, structurally well-defined aggregates joined by noncovalent bonds. Molecular self-assembly is ubiquitous in biological systems and underlies the formation of a wide variety of complex biological structures. Understanding self-assembly and the associated noncovalent interactions that connect complementary interacting molecular surfaces in biological aggregates is a central concern in structural biochemistry. Self-assembly is also emerging as a new strategy in chemical synthesis, with the potential of generating nonbiological structures with dimensions of 1 to 10(2) nanometers (with molecular weights of 10(4) to 10(10) daltons). Structures in the upper part of this range of sizes are presently inaccessible through chemical synthesis, and the ability to prepare them would open a route to structures comparable in size (and perhaps complementary in function) to those that can be prepared by microlithography and other techniques of microfabrication.

Molecular self-assembly and nanochemistry: A chemical strategy for the synthesis of nanostructures

Lignin, a major component of lignocellulose, is the largest source of aromatic building blocks on the planet and harbors great potential to serve as starting material for the production of biobased products. Despite the initial challenges associated with the robust and irregular structure of lignin, the valorization of this intriguing aromatic biopolymer has come a long way: recently, many creative strategies emerged that deliver defined products via catalytic or biocatalytic depolymerization in good yields. The purpose of this review is to provide insight into these novel approaches and the potential application of such emerging new structures for the synthesis of biobased polymers or pharmacologically active molecules. Existing strategies for functionalization or defunctionalization of lignin-based compounds are also summarized. Following the whole value chain from raw lignocellulose through depolymerization to application whenever possible, specific lignin-based compounds emerge that could be in the fu...

Bright Side of Lignin Depolymerization: Toward New Platform Chemicals

Ionic liquids are remarkable chemical compounds, which find applications in many areas of modern science. Because of their highly tunable nature and exceptional properties, ionic liquids have become essential players in the fields of synthesis and catalysis, extraction, electrochemistry, analytics, biotechnology, etc. Apart from physical and chemical features of ionic liquids, their high biological activity has been attracting significant attention from biochemists, ecologists, and medical scientists. This Review is dedicated to biological activities of ionic liquids, with a special emphasis on their potential employment in pharmaceutics and medicine. The accumulated data on the biological activity of ionic liquids, including their antimicrobial and cytotoxic properties, are discussed in view of possible applications in drug synthesis and drug delivery systems. Dedicated attention is given to a novel active pharmaceutical ingredient-ionic liquid (API-IL) concept, which suggests using traditional drugs in ...

Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine.

Supramolecular Amphiphiles Based on Host-Guest Molecular Recognition Motifs.

The formation of well-ordered nanostructures through self-assembly of diverse organic and inorganic building blocks has drawn much attention owing to their potential applications in biology and chemistry. Among all organic building blocks, peptides are one of the most promising platforms due to their biocompatibility, chemical diversity, and resemblance to proteins. Inspired by the protein assembly in biological systems, various self-assembled peptide structures have been constructed using several amino acids and sequences. This review focuses on this emerging area, the recent advances in peptide self-assembly, and formation of different nanostructures, such as tubular structures, fibers, vesicles, and spherical and rod-coil structures. While different peptide nanostructures have been discovered, potential applications are explored in drug delivery, tissue engineering, wound healing, and surfactants.

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Self-assembly of peptides to nanostructures

The intracellular delivery of biologically active cargos by employing linear cell-penetrating peptides (CPPs) has been previously reported. Conjugation to linear cationic CPPs, such as TAT (trans-acting activator of transcription; a peptide derived from the HIV-1 transactivator protein), 3] penetratin, antennapedia, or oligoarginine, efficiently enhances the cellular uptake through different mechanisms. The cellular uptake and internalization of many CPPs along with the conjugated cargo occurs predominantly by an endocytic pathway that involves macropinocytosis, a caveolae pathway, clathrin-mediated endocytosis, or lipid-raft dependent endocytosis. Endosomal uptake represents a major challenge in targeted intracellular drug delivery since some compounds are trapped in endosomes and cannot reach the biological targets in the cytoplasm or nucleus. Thus, strategies that promote endosomal escape or avoid endosomal routes are required for improving bioavailability. Moreover, the nuclear delivery of cell-impermeable and water-insoluble molecules remains a major challenge. The nucleus is a desirable target because the genetic information of the cell and transcription machinery resides there. To date, most approaches for nuclear delivery of compounds have taken advantage of covalent conjugation, which requires release of the cargo from the conjugate and/or endosomal escape. There is therefore a need to develop alternative stable peptide carriers that avoid endosomal pathways and/or covalent conjugation. Compared to linear peptides that are susceptible to hydrolysis by endogenous peptidases, cyclic peptides are enzymatically more stable. The cell-penetrating properties and application of homochiral l-cyclic peptides in drug delivery remain unexplored. Previous studies on linear CPPs by our research group and others indicated that an optimal balance of positive charge and hydrophobicity is required for interactions with the cell membrane and deep penetration into the lipid bilayer. 4,8–10] Herein, we report the design and evaluation of amphipathic homochiral l-cyclic peptides for potential applications as CPPs and/or as molecular transporters of bioactive compounds. Eleven cyclic peptides, namely [WR]4, [FK]4, [AK]4, [EL]4, [RFEF]2, [EK]4, [ER]4, [FR]4, [RFE]3, [WR]3, and [WR]5 (Scheme 1), which contain l-amino acids, were synthesized by employing 9-fluorenylmethyloxycarbonyl (Fmoc) based peptide chemistry. The selection of the cyclic peptides was based on the presence of hydrophobic residues (e.g., W, F, L) and charged residues (e.g., K, R, E). We hypothesized that an optimal amphipathic cyclic peptide that contains appropriate residues, and that undergoes intermolecular and intramolecular interactions can act as a CPP and/or entrap and deliver a bioactive compound intracellularly. To examine the potential application of the cyclic peptides as molecular transporters, a model experiment was performed with lamivudine (( )-2’,3’-dideoxy-3’-thiacytidine, 3TC). 3TC is a nucleoside reverse transcriptase inhibitor that blocks HIV-1 and hepatitis B virus replication. The efficient cellular uptake of 3TC is critical for effective antiviral activity. To monitor the molecular transport ability of the cyclic peptides, a carboxyfluorescein derivative of 3TC (F-3TC) was synthesized. The cellular uptake of the fluorescently labeled 3TC (F3TC) was examined in the leukemia CCRF-CEM cell line in the presence or absence of cyclic peptides. After 1 h incubation at 37 8C, the cells were treated with trypsin to remove the cell-surface-bound drug. The cellular uptake of F3TC was monitored by fluorescence-activated cell sorting (FACS; Figure 1a) and fluorescence microscopy (Figure 1b). The cyclic peptides did not exhibit any cytotoxicity by using an MTT assay at an experimental concentration of 50 mm in four different cell lines, namely CCRF-CEM, HT-29, MDAMD-468, and SK-OV-3, thus showing consistent results (Figure S12). FACS and fluorescence microscopy showed significantly higher fluorescence signals in the cells treated with F-3TCloaded [WR]4 and [WR]5 compared to those treated with other F-3TC-loaded cyclic peptides and with F-3TC alone, thus suggesting that the uptake of F-3TC is facilitated by [WR]n (n = 4, 5) and is dependent on nature of amino acids. F3TC-loaded [WR]5 exhibited a cellular uptake that was approximately five times higher than that of F-3TC alone (Figure 1a). Phosphopeptides are valuable probes for studying phosphoprotein–protein interactions because these peptides mimic the interactions between the negatively charged phosphate group of phosphoproteins and positively charged amino acids in the binding pockets of a number of proteins. Studying negatively charged phosphopeptides in cellular systems is challenging because these peptides do not readily [*] Dr. D. Mandal, A. Nasrolahi Shirazi, Prof. K. Parang Department of Biomedical and Pharmaceutical Sciences University of Rhode Island 41 Lower College Road, Kingston, RI 02881 (USA) E-mail: kparang@uri.edu

Cell-penetrating homochiral cyclic peptides as nuclear-targeting molecular transporters.

Doxorubicin (Dox) is a hydrophilic anticancer drug that has short retention time due to the efficient efflux in some cancer cells (e.g., ovarian adenocarcinoma SK-OV-3). Cyclic [W(RW)(4)] and the corresponding linear peptide (RW)(4) were conjugated with Dox through an appropriate linker to afford cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox conjugates to enhance the cellular uptake and cellular retention of the parent drug for sustained anticancer activity. Comparative antiproliferative assays between covalent (cyclic [W(RW)(4)]-Dox and linear (RW)(4)-Dox) and the corresponding noncovalent physical mixtures of the peptides and Dox were performed. Cyclic [W(RW)(4)]-Dox inhibited the cell proliferation of human leukemia (CCRF-CEM) (62-73%), ovarian adenocarcinoma (SK-OV-3) (51-74%), colorectal carcinoma (HCT-116) (50-67%), and breast carcinoma (MDA-MB-468) (60-79%) cells at a concentration of 1 μM after 72-120 h of incubation. Cyclic [W(RW)(4)]-Dox exhibited higher antiproliferative activity than linear (RW)(4)-Dox in all cancer cells with the highest activity observed after 72 h. Flow cytometry analysis showed 3.6-fold higher cellular uptake of cyclic [W(RW)(4)]-Dox than Dox alone in SK-OV-3 cells after 24 h incubation. The cellular hydrolysis study showed that 99% of cyclic [W(RW)(4)]-Dox was hydrolyzed intracellularly within 72 h and released Dox. These data suggest that cyclic [W(RW)(4)]-Dox can be used as a potential prodrug for improving the cellular delivery and retention of Dox.

Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs.

A number of cyclic peptides were synthesized and evaluated as simultaneous reducing and capping agents for generation of cyclic peptide-capped gold nanoparticles (CP-AuNPs). Among them, direct dissolution of cyclic peptides containing alternate arginine and tryptophan [WR]n (n = 3–5) into an aqueous solution of AuCl4– led to the formation of CP-AuNPs, through the reducing activity of tryptophan residues and attraction of positively charged arginine residues toward chloroaurate anions in the reaction environment. Differential interference contrast microscopy of fluorescence-labeled lamivudine in the presence of [WR]4-capped AuNPs showed significantly higher cellular delivery of antiviral drug versus that of parent drug alone. Flow cytometry studies also showed that the cellular uptake of fluorescence-labeled lamivudine, emtricitabine, and stavudine was significantly enhanced in human ovarian adenocarcinoma (SK-OV-3) cells in the presence of [WR]4-AuNPs. For example, fluorescence labeled lamivudine-loaded [...

Cyclic peptide-capped gold nanoparticles as drug delivery systems

Many of the reported arginine-rich cell-penetrating peptides (CPPs) for the enhanced delivery of drugs are linear peptides composed of more than seven arginine residues to retain the cell penetration properties. Herein, we synthesized a class of nine polyarginine peptides containing 5 and 6 arginines, namely, R5 and R6. We further explored the effect of acylation with long chain fatty acids (i.e., octanoic acid, dodecanoic acid, and hexadecanoic acid) and cyclization on the cell penetrating properties of the peptides. The fluorescence-labeled acylated cyclic peptide dodecanoyl-[R5] and linear peptide dodecanoyl-(R5) showed approximately 13.7- and 10.2-fold higher cellular uptake than that of control 5,6-carboxyfluorescein, respectively. The mechanism of the peptide internalization into cells was found to be energy-dependent endocytosis. Dodecanoyl-[R5] and dodecanoyl-[R6] enhanced the intracellular uptake of a fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI) in human ova...

Amir Nasrolahi Shirazi

Papers

Self-assembly of peptides to nanostructures

Cell-penetrating homochiral cyclic peptides as nuclear-targeting molecular transporters.

Design and biological evaluation of cell-penetrating peptide-doxorubicin conjugates as prodrugs.

Cyclic peptide-capped gold nanoparticles as drug delivery systems

Enhanced Cellular Uptake of Short Polyarginine Peptides through Fatty Acylation and Cyclization