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Development of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase with antiparasitic activity in vitro
No full textENZYME INHIBITORS AS POTENTIAL ANTIPARASITIC AGENTS
Get PDFAbstract of the PhD thesis
ENZYME INHIBITORS AS POTENTIAL ANTIPARASITIC AGENTS
PhD course in Chemistry, XXIX cycle, University of Milan
PhD student: Gregorio Cullia (R10447)
Tutor: Prof. Paola Conti
Co-tutor: Dr. Lucia Tamborini
Protozoan parasitic diseases, such as Malaria and Human African Trypanosomiasis (HAT), have a tremendous health, social and economic impact on people living in tropical and subtropical regions of the world. While around 3.8 billion people are at risk of infection, [1] available treatments are unsatisfactory, mainly due to constantly increasing drug resistance. Hence, there is an urgent need of developing new chemotherapeutic agents acting on new molecular targets, such as essential parasitic enzymes. One selected target is the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of P. falciparum, a key glycolytic enzyme with many other important functions. In this thesis, I describe the development of inhibitors that act alkylating, in a selective way, the catalytic cysteine, inspired by (S,S)-3-bromoacivicin [(S,S)-1]. [2]Some of the inhibitors, in particular (S,S)-9 and (S,S)-59, showed sub-micromolar EC50 toward P. falciparum cultures and a considerably low cytotoxicity toward human cell lines (≥ 20 mM).
In the second project, the interesting 3-bromoisoxazoline warhead was coupled to known peptidic recognition moieties generating new inhibitors of rhodesain(TbCatL), an essential protease involved in virulence and defence processes of the parasite. [3] Some low micromolar inhibitors were identified, among which the diastereoisomeric mixture (S,S,S)-138/(S,R,R)-139 showed also an interesting antiparasitic activity.
The third enzyme that was exploited as target is the N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase (TbFolD), a crucial enzyme involved in the folate pathway. I started synthesizing LY374571 [(S)-149], a known human FolD inhibitor, [4] with the aim of using it as a lead compound: interestingly, following the published synthesis protocol I unambiguously obtained compound (S)-156, with a structure different from the one reported in the literature. I performed a structure-activity relationships study replacing the glutamate tail with other α-, β- and γ-amino acids [compounds (S)-175-181]. Moreover, the first X-ray structure of TbFolD in presence of (S)-156 and NADP+,was obtained. [5]
The last part of this PhD thesis regards the development of new potential agents for the treatment of C. trachomatis infections. This bacterium is the agent trachoma (a neglected tropical disease), an eye infection that causes the impairment of the sight of 1.9 million people, and of one of the most prevalent sexually transmitted infection. [6] In the past, the inhibitory activity of CI-976 (182) of inhibiting human lysophosphatidicacid:acyl-CoA acyl transferase(hLPAAT) was correlated to a delay in the slow recycling pathway of transferrin, that hampered the growth of the bacterium. [7] I performed an exhaustive structure-activity relationships study focusing on the different structural features of 182 (such as the α- and the N- substitutions and the properties of the aromatic ring). Among the synthesized compounds, 185 showed anti-chlamydial activity comparable to 182. This approach represents an innovative strategy to treat microbial infections, based on the inhibition of a trafficking pathway that is disposable for the human host.
References
[1] a. [Online]. Available: http://www.who.int/mediacentre/factsheets/fs094/en/;b. [Online]. Available: http://www.who.int/mediacentre/factsheets/fs259/en/.
[2] S. Bruno, A. Pinto, G. Paredi, L. Tamborini, C. De Micheli, V. La Pietra, L. Marinelli, E. Novellino, P. Conti and A. Mozzarelli, “Discovery of covalent inhibitors of glyceraldehyde-3-phosphate dehydrogenase, a target for the treatment of malaria,” J. Med. Chem., vol. 57, pp. 7465-7471, 2014.
[3] a. R. Ettari, S. Previti, L. Tamborini, G. Cullia, S. Grasso and M. Zappalà, “The inhibition of cysteine proteases rhodesain and TbCatB: a valuable approach to treat human African trypanosomiasis,” Mini-Rev. Med. Chem., 2016; b. R. Ettari, A. Pinto, S. Previti, L. Tamborini, I. C. Angelo, V. La Pietra, L. Marinelli, E. Novellino, T. Schirmeister, M. Zappalà, S. Grasso, C. De Micheli and P. Conti, “Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation,” Bioorg. Med. Chem., vol. 23, pp. 7053-7060, 2015.
[4] A. Schmidt, H. Wu, R. E. MacKenzie, V. J. Chen, J. R. Bewly, J. E. Ray, J. E. Toth and M. Cygler, “Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase,” Biochemistry, vol. 39, pp. 6325-6335, 2000.
[5] T. C. Eadsforth, A. Pinto, R. Luciani, L. Tamborini, G. Cullia, C. De Micheli, L. Marinelli, S. Cosconati, E. Novellino, L. Lo Presti, A. Cordeiro da Silva, P. Conti, W. N. Hunter and M. P. Costi, “Characterization of 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido based inhibitors of TrypanosomabruceiFolD and testing for antiparasitic activity,” J. Med. Chem., vol. 58, no. 20, pp. 7938-7948, 2015.
[6] World Health Organization, “WHO guidelines for the treatment of Chlamydia trachomatis,” 2016. [Online]. Available: http://www.who.int/reproductivehealth/publications/rtis/chlamydia-treatment-guidelines/en/.
[7] a. K. Chambers, B. Judson and W. J. Brown, “A unique lysophospholipidacyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways,” J. Cell Sci., vol. 118, pp. 3061-3071, 2005; b. S. P. Ouellette and R. A. Carabeo, “A functional slow recycling pathway of transferrin is required for growth of Chlamydia,” Front. Microbiol.,vol. 1, 2010
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
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koamabayili/VECTRON-author-checklist: VECTRON author checklist
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Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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