- Development of the Inhibitors that Target the PD-1/PD-L1 Interaction-A Brief Look at Progress on Small Molecules, Peptides and Macrocycles. [Review]
- MMolecules 2019 May 30; 24(11)
- Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-…
Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.
- NMR fragment-based screening for development of the CD44-binding small molecules. [Journal Article]
- BCBioorg Chem 2019; 82:284-289
- The cell-surface protein CD44, a primary receptor for hyaluronic acid (HA), is one of the most promising targets for cancer therapies. It is prominently involved in the process of tumor growth and me…
The cell-surface protein CD44, a primary receptor for hyaluronic acid (HA), is one of the most promising targets for cancer therapies. It is prominently involved in the process of tumor growth and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor is therefore of great importance, yet until now there are only few small molecules reported to bind to CD44. Here, we describe the results of the NMR fragment-based screening conducted against CD44 by which we found eight new hit compounds that bind to the receptor with the affinity in milimolar range. The NMR-based characterization revealed that there are two possible binding modes for these compounds, and for some of them the binding is no longer possible in the presence of hyaluronic acid. This could provide an interesting starting point for the development of new high-affinity ligands targeting the CD44-HA axis.
- From marine caves to the deep sea, a new look at Caminella (Demospongiae, Geodiidae) in the Atlanto-Mediterranean region. [Journal Article]
- ZZootaxa 2018 Aug 31; 4466(1):174-196
- Caminella Lendenfeld, 1894 is a poorly known Geodiidae genus with unclear phylogenetic relationships. In order to find new lines of evidence that could shed light on the evolutionary history of Camin…
Caminella Lendenfeld, 1894 is a poorly known Geodiidae genus with unclear phylogenetic relationships. In order to find new lines of evidence that could shed light on the evolutionary history of Caminella, we decided to revise type material and museum material, as well as examine new material from underwater caves and deep-sea ecosystems. In doing so, we formally show that Isops maculosus Vosmaer, 1894 and Caminella loricata Lendenfeld, 1894 are junior synonyms of Caminella intuta (Topsent, 1892). We discuss different spicule morphological phenotypes in C. intuta, which may be linked to silica availability. We also discovered two new species of deep-sea Caminella: 1) from Cape Verde (Caminella caboverdensis sp. nov.) and 2) from seamounts located south of the Azores archipelago and the North of Spain (Caminella pustula sp. nov.). We reveal that Caminella sterrasters have complex surface microstructures, unique amongst the Geodiidae, where actin tips are linked to each other. Molecular markers (COI, 28S (C1-D2) and 18S) sequenced for some specimens led to new phylogenetic analyses, which continue to suggest a close relationship of Caminella with the Erylinae and Calthropella; these affinities are discussed in light of morphological characters.
- Specific Antibody Fragment Ligand Traps Blocking FGF1 Activity. [Journal Article]
- IJInt J Mol Sci 2018 Aug 21; 19(9)
- Fibroblast growth factor 1 (FGF1) and its receptors (FGFRs) regulate crucial biological processes such as cell proliferation and differentiation. Aberrant activation of FGFRs by their ligands can pro…
Fibroblast growth factor 1 (FGF1) and its receptors (FGFRs) regulate crucial biological processes such as cell proliferation and differentiation. Aberrant activation of FGFRs by their ligands can promote tumor growth and angiogenesis in many tumor types, including lung or breast cancer. The development of FGF1-targeting molecules with potential implications for the therapy of FGF1-driven tumors is recently being considered a promising approach in the treatment of cancer. In this study we have used phage display selection to find scFv antibody fragments selectively binding FGF1 and preventing it from binding to its receptor. Three identified scFv clones were expressed and characterized with regard to their binding to FGF1 and ability to interfere with FGF1-induced signaling cascades activation. In the next step the scFvs were cloned to scFv-Fc format, as dimeric Fc fusions prove beneficial in prospective therapeutic application. As expected, scFvs-Fc exhibited significantly increased affinity towards FGF1. We observed strong antiproliferative activity of the scFvs and scFvs-Fc in the in vitro cell models. Presented antibody fragments serve as novel FGF1 inhibitors and can be further utilized as powerful tools to use in the studies on the selective cancer therapy.
- Identification of small-molecule inhibitors of USP2a. [Journal Article]
- EJEur J Med Chem 2018 Apr 25; 150:261-267
- USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo a…
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
- Spectroscopic and Theoretical Studies of Fluorescence Effects in 2-Methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole Induced by Molecular Aggregation. [Journal Article]
- JFJ Fluoresc 2018; 28(1):65-77
- The article presents the results of fluorescence analyses of 2-methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (MDFT) in an aqueous environment. MDFT dissolved in aqueous solutions with a pH va…
The article presents the results of fluorescence analyses of 2-methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (MDFT) in an aqueous environment. MDFT dissolved in aqueous solutions with a pH value in the range from 1 to 4.5 yielded an interesting effect of two clearly separated fluorescence emissions. In turn, a single fluorescence was observed in MDFT dissolved in water solutions with a pH value from 4.5 to 12. As it was suggested in the previous investigations of other 1,3,4-thiadiazole compounds, these effects may be associated with conformational changes in the structure of the analysed molecule accompanied by aggregation effects. Crystallographic data showed that the effect of the two separated fluorescence emissions occurred in a conformation with the -OH group in the resorcyl ring bound on the side of the sulphur atom from the 1,3,4-thiadiazole ring. The hypothesis of aggregation as the mechanism involved in the change in the spectral properties at low pH is supported by the results of (Time-Dependent) Density Functional Theory calculations. The possibility of rapid analysis of conformational changes with the fluorescence spectroscopy technique may be rather important outcome obtained from the spectroscopic studies presented in this article. Additionally, the presented results seem to be highly important as they can be easily observed in solutions and biologically important samples.
- Phylogenetic classification of yeasts and related taxa within Pucciniomycotina. [Journal Article]
- SMStud Mycol 2015; 81:149-89
- Most small genera containing yeast species in the Pucciniomycotina (Basidiomycota, Fungi) are monophyletic, whereas larger genera including Bensingtonia, Rhodosporidium, Rhodotorula, Sporidiobolus an…
Most small genera containing yeast species in the Pucciniomycotina (Basidiomycota, Fungi) are monophyletic, whereas larger genera including Bensingtonia, Rhodosporidium, Rhodotorula, Sporidiobolus and Sporobolomyces are polyphyletic. With the implementation of the "One Fungus = One Name" nomenclatural principle these polyphyletic genera were revised. Nine genera, namely Bannoa, Cystobasidiopsis, Colacogloea, Kondoa, Erythrobasidium, Rhodotorula, Sporobolomyces, Sakaguchia and Sterigmatomyces, were emended to include anamorphic and teleomorphic species based on the results obtained by a multi-gene phylogenetic analysis, phylogenetic network analyses, branch length-based methods, as well as morphological, physiological and biochemical comparisons. A new class Spiculogloeomycetes is proposed to accommodate the order Spiculogloeales. The new families Buckleyzymaceae with Buckleyzyma gen. nov., Chrysozymaceae with Chrysozyma gen. nov., Microsporomycetaceae with Microsporomyces gen. nov., Ruineniaceae with Ruinenia gen. nov., Symmetrosporaceae with Symmetrospora gen. nov., Colacogloeaceae and Sakaguchiaceae are proposed. The new genera Bannozyma, Buckleyzyma, Fellozyma, Hamamotoa, Hasegawazyma, Jianyunia, Rhodosporidiobolus, Oberwinklerozyma, Phenoliferia, Pseudobensingtonia, Pseudohyphozyma, Sampaiozyma, Slooffia, Spencerozyma, Trigonosporomyces, Udeniozyma, Vonarxula, Yamadamyces and Yunzhangia are proposed to accommodate species segregated from the genera Bensingtonia, Rhodosporidium, Rhodotorula, Sporidiobolus and Sporobolomyces. Ballistosporomyces is emended and reintroduced to include three Sporobolomyces species of the sasicola clade. A total of 111 new combinations are proposed in this study.
- [Rickettsiosis - Early skin biopsy is essential because of latency in serological findings]. [Case Reports]
- DMDtsch Med Wochenschr 2016; 141(5):343-5
- Global travel increasis practitioner's confrontation with very special infectious diseases, like hemorrhagic viral diseases that are traditionally rare in European countries. Prompt diagnosis and sub…
Global travel increasis practitioner's confrontation with very special infectious diseases, like hemorrhagic viral diseases that are traditionally rare in European countries. Prompt diagnosis and subsequent induction of therapy are essential to prevent high rates of severe and lethal complications.
- White Rust of Echinacea angustifolia and E. purpurea in North America Caused by a Pustula Species. [Journal Article]
- PDPlant Dis 2014; 98(6):856
- In 2012 and 2013, foliar symptoms were observed in certified organic, 2- to 4-ha crops of Echinacea angustifolia and E. purpurea in Grant and Klickitat counties, WA. White pustules were predominant o…
In 2012 and 2013, foliar symptoms were observed in certified organic, 2- to 4-ha crops of Echinacea angustifolia and E. purpurea in Grant and Klickitat counties, WA. White pustules were predominant on the abaxial leaf surface, increased in number, and coalesced on E. angustifolia, with 100% infection by the end of the season; in contrast, symptoms remained sparse on E. purpurea. Symptomatic leaves of each species were collected in May 2013 in Grant Co. Sori and sporangia were typical of those of white rust on Asteraceae caused by Pustula obtusata (1), originally named Albugo tragopogonis, then P. tragopogonis (4). Hyaline sporangia (n = 50) averaged 21 ± 2 × 20 ± 2 μm (16 to 25 × 16 to 24 μm) with a 2.6 ± 0.8 μm (1.0 to 4.0 μm) thick wall. Honey-colored to dark brown oospores were embedded in the abaxial leaf surface surrounding sori on older leaves. Oospores (n = 50) averaged 75 ± 7 × 63 ± 6 μm (60 to 96 × 52 to 76 μm) and 52 ± 4 × 51 ± 4 μm (44 to 65 × 44 to 60 μm) with (including protruberances) and without the hyaline outer wall, respectively. Sori were excised and shaken in 100 ml cold (4°C), deionized water at 400 rpm for 15 min on a gyrotory shaker. DNA extracted from the resulting spore suspension was subjected to a PCR assay using oomycete specific primers (2) to amplify the cytochrome oxidase subunit II (cox2) region of mtDNA (3). The 511-nt consensus sequence of the PCR product (GenBank Accession No. KF981439) was 98% identical to a cox2 sequence of A. tragopogonis from sunflower (Helianthus annuus) (AY286221.1), and 96% identical to cox2 sequences of P. tragopogonis (GU292167.1 and GU292168.1) (= P. obtusata) (1,2,4). Pathogenicity of the white rust isolate was confirmed by inoculating 49-day-old plants of E. angustifolia and E. purpurea with a spore suspension prepared as described above. One plant/species was placed in each of six clear plastic bags in a growth chamber at 18°C with a 12-h day/12-h night cycle for 48 h. Five replicate sets of one plant/species were each inoculated with 2.2 × 105 spores/ml on the adaxial and abaxial leaf surfaces using an airbrush (8 psi). One plant/species was sprayed with water as a control treatment. The plants were resealed in the bags for 48 h. After 7 days, white pustules were observed on at least one plant species. The plants were placed in plastic bags again overnight, and re-inoculated with 2.9 × 105 spores/ml. In addition, two sunflower plants at the 4-true-leaf stage were incubated in each of two plastic bags overnight, and inoculated with the spore suspension. Two additional sunflower plants were treated with water as control plants. All plants were removed from the bags after 48 h. White rust sori with sporangia developed on all inoculated Echinacea plants within 10 days, but not on control plants of either species, nor inoculated and non-inoculated sunflower plants, verifying that the pathogen was not P. helianthicola (1,2). Since the cox2 sequence was closest to that of a sunflower white rust isolate, the pathogen appears to be closer to P. helianthicola than P. obtusata, and may be a new Pustula species. To our knowledge, this is the first documentation of white rust on E. angustifolia and E. purpurea in North America. The severity of white rust on E. angustifolia highlights the need for effective management practices. References: (1) C. Rost and M. Thines. Mycol. Progress 11:351, 2012. (2) O. Spring et al. Eur. J. Plant Pathol 131:519, 2011. (3) S. Telle and M. Thines. PloS ONE 3(10):e3584, 2008. (4) M. Thines and O. Spring. Mycotaxon 92:443, 2005.
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- Oospores of Pustula helianthicola in sunflower seeds and their role in the epidemiology of white blister rust. [Journal Article]
- IFIMA Fungus 2013; 4(2):251-8
- White blister rust (WBR) of sunflower caused by Pustula helianthicola is an important and often underestimated disease in many countries of the world. The epidemiology of the pathogen is not yet full…
White blister rust (WBR) of sunflower caused by Pustula helianthicola is an important and often underestimated disease in many countries of the world. The epidemiology of the pathogen is not yet fully understood; particularly the role of oospores in primary infection and long distance dispersal. We analysed WBR severity in sunflower under natural conditions and found disease incidence of 97-99 % in fields where infected sunflower had first been observed ca. 8 yr ago. Besides the typical blisters of mitotic sporangia on leaves, large amounts of oospores were observed on the involucral bracts. Inoculation of sunflower seedlings with oospores from these bracts resulted in disease incidence of ca. 30 %, thus confirming their infectivity without a period of dormancy. Bracts of infected flower heads from the field were checked for oospores using a binocular microscope and seeds were checked by light microscopy. Oospores were found in all of the bracts and in up to 28 % of the achenes. Light microscopy revealed that oospores developed in the thin-walled, crushed parenchymatic cells of the inner layer and in the parenchymatic rays of the fibrous layer of the pericarp. Dried seeds were grown in soil to assess the occurrence of seed borne infection. Within 3 wk, up to 58 % of seedlings showed typical WBR pustules on cotyledons. Asymptomatic infections were confirmed in phenotypically healthy plants by using a PCR-based diagnostic test for P. helianthicola. The results showed the importance of oospores of P. helianthicola as the primary inoculum for WBR development in sunflower, and pointed to the potential role of contaminated seeds in the long distance transmission of the pathogen.