Spotlight pubs.acs.org/crt
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NANOPARTICLE-CONJUGATED TISSUE-HOMING LYMPHOCYTES AS CHEMOTHERAPEUTIC DELIVERY VECTORS Lymphomas are hematological cancers that disseminate throughout the body and can seed tumors in multiple organs. Successful chemotherapeutic treatment may be limited by poor uptake of drugs in lymph nodes, common sites of metastasis that may serve as tumor sanctuaries. Darrell J. Irvine led a team that engineered autologous lymphocytes to carry drug-loaded nanoparticles to tumor sites; these T cells intrinsically migrate to lymphoid tissues and directly deliver chemotherapeutics to lymphomas disseminated there ((2015) Sci. Transl. Med., 7, 291ra94). The scientists covalently conjugated controlled-release lipid nanocapsules (NCs) to the membranes of primary polyclonal T cells that do not specifically recognize tumor cell antigens but express lymph node-homing receptors. The NCs contained the topoisomerase I poison, SN-38, a highly potent active drug with limited in vivo efficacy due to poor pharmacokinetics. These functionalized T cells are resistant to SN-38 and can safely and efficiently carry therapeutic doses of the drug to lymphoid organs. The authors injected the drug-loaded T cells into mice infected with a murine model of Burkitt’s lymphoma. The SN-38 NC-conjugated T cells migrated to the lymph nodes, spleen, and bone marrow, resulting in local chemotherapeutic concentrations over 60-fold higher than those seen when free SN-38 was administered systemically. High drug levels persisted for over 4 days, significantly reducing tumor burden and prolonging survival in animals without adverse effects. This tissue-specific T cell-mediated chemotherapeutic delivery successfully transported the drug directly to lymph nodes and concentrated it there, enhancing its potency and reducing systemic toxicity. Abigail Druck Shudofsky
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LYSINE MOLECULAR TWEEZERS MODULATE P53 AGGREGATION
the effect of CLR01 on p53 mutants ((2015) Biochemistry, 54, 3729−3738). The authors found that when CLR01 binds to mutant p53DBD its hydrophobic side arms induce swift formation of β-sheet-rich, intermediate-size aggregates. However, CLR01 inhibits later aggregation of mutant p53DBD in a dose-dependent manner and protects cells from toxic effects of preformed aggregates. p53 structural mutants have an exposed aggregationnucleating sequence usually hidden in the DBD hydrophobic core; likely, CLR01 selectively binds exposed Lys residues, interfering with hydrophobic and electrostatic interactions that play a role in protein oligomerization and aggregation. Abigail Druck Shudofsky
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IDENTIFICATION OF A SNAKE-DERIVED BROAD-SPECTRUM ANTIMICROBIAL PEPTIDE WITH ANTI-INFLAMMATORY ACTIVITY
Reprinted from Sinha et al. (2011) J. Am. Chem. Soc., 133, 16958−16969. Copyright 2011 American Chemical Society.
The cell-cycle-regulating transcription factor p53 is a homotetramer with two disordered domains bordering two core folded domains, including the DNA binding domain (DBD). The DBD is unstable and rapidly and reversibly unfolds at physiological temperatures. Unfolded p53 can denature irreversibly and form small soluble aggregates that polymerize into high-molecularweight, β-sheet-rich aggregates similar to amyloid deposits seen in protein misfolding diseases. While folded and unfolded p53 are typically in equilibrium, some conformational mutants are predominantly unfolded resulting in the accumulation of cytotoxic amyloid-like structures. Small-molecule modulators that interfere with mutant p53 aggregation may avert its harmful effects. Lysine (Lys)-specific molecular tweezers, such as CLR01, are made of two hydrocarbon arms that can interact with the alkyl side chains of Lys residues and have negatively charged headgroups that interact with the Lys NH3+ group. Because they can selectively inhibit amyloid protein aggregation and toxicity, Daniel Segal and collaborators examined © 2015 American Chemical Society
This research was originally published in Journal of Biological Chemistry. Wei et al. (2015) Identification and characterization of the first cathelicidin from sea snakes with potent antimicrobial and anti-inflammatory activity, and special mechanism. J. Biol. Chem., 290, 16633−16652. Copyright the American Society for Biochemistry and Molecular Biology.
Cathelicidins are small antimicrobial peptides that play a critical role in the innate immune response by actively resisting bacterial, Published: August 17, 2015 1517
DOI: 10.1021/acs.chemrestox.5b00292 Chem. Res. Toxicol. 2015, 28, 1517−1518
Chemical Research in Toxicology
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viral, fungal, and parasitic invasions. They are composed of an N-terminus signal peptide sequence, a highly conserved cathelin domain, and a variable C-terminus mature peptide sequence. While cathelicidins are present in many vertebrates, none have been found in marine reptiles before Yipeng Wang and collaborators identified and characterized the novel Hc-CATH from the sea snake, Hydrophis cyanocinctus ((2015) J. Biol. Chem., 290, 16633−16652). The 30 amino acid polypeptide was present in the venom gland, skin, lung, and spleen of the sea snake. Hc-CATH displayed potent, rapid, and broad-spectrum antimicrobial activity against 35 strains of human micropathogens and 11 aquatic pathogenic bacteria. Its antimicrobial activity is salt-resistant and thermally tolerant. The researchers found that Hc-CATH is amphipathic and primarily adopts an α-helical conformation in hydrophobic or membrane-mimetic environments. Its antimicrobial and anti-inflammatory activity is dependent on this structure; Hc-CATH directly binds to bacterial lipopolysaccharides through electrostatic interactions, permeabilizes and disrupts microbial membranes, and lyses cells. This binding also blocks pro-inflammatory cytokine production and other signaling pathways in a dose-dependent manner by inhibiting receptor binding. Hc-CATH is very stable in aqueous solutions with a low cytotoxicity to mammalian cells and is a potent candidate for an anti-infective agent. Abigail Druck Shudofsky
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Spotlight
A PEGYLATED GD3+-BINDING PROTEIN IS A NOVEL MRI CONTRAST AGENT
Reprinted with permission from Xue et al. (2015) Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. PNAS, 112, 6607−6612. Copyright 2015 National Academy of Sciences.
Magnetic resonance imaging (MRI) scans use magnetism to polarize the hydrogen nuclei of water in tissues; the water distribution allows the acquisition of high-resolution images. Designated contrast agents containing paramagnetic metal ions can modify the timing of when protons “relax” and their net magnetization returns to equilibrium, improving intensity and visibility of internal structures. Liver imaging is difficult since the organ rapidly excretes contrast agents; limitations on MRI sensitivity offer no reliable way to detect early stage hepatic metastases and primary liver cancer. Jenny J. Yang led a team who designed a protein-based MRI contrast agent, ProCA32-P40, which allows for detection of early liver metastases ∼100-fold smaller than the present detection threshold ((2015) Proc. Natl. Acad. Sci. U.S.A, 112, 6607−6612). Paramagnetic gadolinium (Gd3+) is often used for contrast, but it has a low relaxivity and its use is limited to sites where it can accumulate in high concentrations. The authors introduced two point mutations into α-parvalbumin, a Ca2+-binding protein, to engineer high-affinity Gd3+ binding pockets. This resulted in ProCA32, a contrast agent with the highest metal selectivity of all reported Gd3+-based contrast agents and a high relaxivity with no toxicity to cells or organs. The authors further improved biocompatibilities through PEGylation; ProCA32-P40 has significantly increased retention time along with solubility, stability, and preferential liver distribution. The improved kidney, blood, and liver pharmacokinetics of ProCA32-P40 allows for sensitive, high-quality imaging of liver metastasis. Abigail Druck Shudofsky
VITAMIN D STATUS ALTERS HIV INFECTION RESPONSE
Vitamin D is a critical secosteroid that enhances mineral absorption. Previtamin D3 is synthesized in keratinocytes when UVB photons react with 7-dehydrocholesterol. Skin pigmentation regulates UV penetration, as eumelanin competes for UVB photons; individuals with high eumelanin content (and consequently darker skin) need greater UVB exposure for D3 synthesis and are more susceptible to vitamin D deficiency. Vitamin D deficiency is associated with increased cellular permissiveness to HIV-1 infection. Nina G. Jablonski and collaborators conducted a longitudinal study of healthy young adults in Cape Town, South Africa, where UVB levels decline significantly in the winter and the risk of HIV-1 infection is high. The authors looked at two ethnic groups with moderate-to-dark skin pigmentation and investigated if seasonal vitamin D variation and vitamin D supplementation impact HIV immunity ((2015) Proc. Natl. Acad. Sci. U.S.A., 112, 8052−8057). The researchers found that personal UVB exposure was the major determinant of vitamin D status and varied by season. Xhosa participants with darker pigmentation received more sun exposure and had higher serum vitamin D levels in the summer than the lighter-pigmented Cape Mixed participants did; UVB exposure for both groups dropped over 10-fold in the winter, resulting in a high rate of vitamin D3 deficiency. The authors looked at the ability of HIV-1 to infect immune cells isolated from study participants; the virus could productively replicate in cells obtained in the winter but not in the summer, a seasonal variation that was negated after 6 weeks of oral D3 intake. They found that D3 supplementation stimulates immune cell counts and function and suppresses productive HIV-1 infection, offering a simple intervention to reduce disease progression. Abigail Druck Shudofsky 1518
DOI: 10.1021/acs.chemrestox.5b00292 Chem. Res. Toxicol. 2015, 28, 1517−1518
