Literature DB >> 23372180

VNI cures acute and chronic experimental Chagas disease.

Fernando Villalta1, Mark C Dobish, Pius N Nde, Yulia Y Kleshchenko, Tatiana Y Hargrove, Candice A Johnson, Michael R Waterman, Jeffrey N Johnston, Galina I Lepesheva.   

Abstract

Chagas disease is a deadly infection caused by the protozoan parasite Trypanosoma cruzi. Afflicting approximately 8 million people in Latin America, Chagas disease is now becoming a serious global health problem proliferating beyond the traditional geographical borders, mainly because of human and vector migration. Because the disease is endemic in low-resource areas, industrial drug development has been lethargic. The chronic form remains incurable, there are no vaccines, and 2 existing drugs for the acute form are toxic and have low efficacy. Here we report the efficacy of a small molecule, VNI, including evidence of its effectiveness against chronic Chagas disease. VNI is a potent experimental inhibitor of T. cruzi sterol 14α-demethylase. Nontoxic and highly selective, VNI displays promising pharmacokinetics and administered orally to mice at 25 mg/kg for 30 days cures, with 100% cure rate and 100% survival, the acute and chronic T. cruzi infection.

Entities:  

Keywords:  Chagas disease; Trypanosoma cruzi; VNI; drug discovery; inhibition; sterol 14alpha-demethylase (CYP51); sterol biosynthesis

Mesh：

Substances：

Year:  2013        PMID： 23372180      PMCID： PMC3698996          DOI： 10.1093/infdis/jit042

Source DB:  PubMed          Journal:  J Infect Dis        ISSN： 0022-1899            Impact factor:   5.226


  44 in total

1.  Infectious diseases. Drug developers finally take aim at a neglected disease.

Authors:  Mitch Leslie
Journal:  Science       Date:  2011-08-19       Impact factor: 47.728

Review 2.  Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51).

Authors:  Galina I Lepesheva; Fernando Villalta; Michael R Waterman
Journal:  Adv Parasitol       Date:  2011       Impact factor: 3.870

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Authors:  R L Tarleton; L Zhang; M O Downs
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4.  The adipocyte as an important target cell for Trypanosoma cruzi infection.

Authors:  Terry P Combs; Shankar Mukherjee; Cecilia J G de Almeida; Linda A Jelicks; William Schubert; Ying Lin; David S Jayabalan; Dazhi Zhao; Vicki L Braunstein; Shira Landskroner-Eiger; Aisha Cordero; Stephen M Factor; Louis M Weiss; Michael P Lisanti; Herbert B Tanowitz; Philipp E Scherer
Journal:  J Biol Chem       Date:  2005-04-18       Impact factor: 5.157

5.  Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi.

Authors:  Lívia de Figueiredo Diniz; Ivo Santana Caldas; Paulo Marcos da Matta Guedes; Geovam Crepalde; Marta de Lana; Cláudia Martins Carneiro; André Talvani; Julio Alberto Urbina; Maria Terezinha Bahia
Journal:  Antimicrob Agents Chemother       Date:  2010-04-19       Impact factor: 5.191

6.  Rational modification of a candidate cancer drug for use against Chagas disease.

Authors:  James M Kraus; Christophe L M J Verlinde; Mandana Karimi; Galina I Lepesheva; Michael H Gelb; Frederick S Buckner
Journal:  J Med Chem       Date:  2009-03-26       Impact factor: 7.446

7.  Murine model of a disseminated infection by the novel fungus Fonsecaea monophora and successful treatment with posaconazole.

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Journal:  Antimicrob Agents Chemother       Date:  2009-12-14       Impact factor: 5.191

8.  Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: synthesis and biological properties.

Authors:  Yasutsugu Ueda; John D Matiskella; Jerzy Golik; Timothy P Connolly; Thomas W Hudyma; Srini Venkatesh; Mandar Dali; Shin-Hong Kang; Nancy Barbour; Ravi Tejwani; Sailesh Varia; Jay Knipe; Ming Zheng; Marina Mathew; Kathy Mosure; Junius Clark; Lucinda Lamb; Ivette Medin; Qi Gao; Stella Huang; Chung-Pin Chen; Joanne J Bronson
Journal:  Bioorg Med Chem Lett       Date:  2003-11-03       Impact factor: 2.823

9.  Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth.

Authors:  Galina I Lepesheva; Robert D Ott; Tatiana Y Hargrove; Yuliya Y Kleshchenko; Inge Schuster; W David Nes; George C Hill; Fernando Villalta; Michael R Waterman
Journal:  Chem Biol       Date:  2007-11

10.  Ergosterol biosynthesis and drug development for Chagas disease.

Authors:  Julio A Urbina
Journal:  Mem Inst Oswaldo Cruz       Date:  2009-07       Impact factor: 2.743
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  55 in total

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Authors:  Tyler A Davis; Anna E Vilgelm; Ann Richmond; Jeffrey N Johnston
Journal:  J Org Chem       Date:  2013-10-15       Impact factor: 4.354

2.  Successful Aspects of the Coadministration of Sterol 14α-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi.

Authors:  Francisca Hildemagna Guedes-da-Silva; Denise da Gama Jaén Batista; Cristiane França Da Silva; Beatriz Philot Pavão; Marcos Meuser Batista; Otacílio Cruz Moreira; Letícia Rocha Quintino Souza; Constança Britto; Girish Rachakonda; Fernando Villalta; Galina I Lepesheva; Maria de Nazaré Correia Soeiro
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3.  A new chemotype with promise against Trypanosoma cruzi.

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Journal:  Bioorg Med Chem Lett       Date:  2019-10-31       Impact factor: 2.823

Review 4.  Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi.

Authors:  Cristina Fonseca-Berzal; Vicente J Arán; José A Escario; Alicia Gómez-Barrio
Journal:  Parasitol Res       Date:  2018-09-19       Impact factor: 2.289

5.  Novel 3-nitrotriazole-based amides and carbinols as bifunctional antichagasic agents.

Authors:  Maria V Papadopoulou; William D Bloomer; Galina I Lepesheva; Howard S Rosenzweig; Marcel Kaiser; Benjamín Aguilera-Venegas; Shane R Wilkinson; Eric Chatelain; Jean-Robert Ioset
Journal:  J Med Chem       Date:  2015-01-23       Impact factor: 7.446

6.  Complexes of Trypanosoma cruzi sterol 14α-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity.

Authors:  Tatiana Y Hargrove; Zdzislaw Wawrzak; Paul W Alexander; Jason H Chaplin; Martine Keenan; Susan A Charman; Catherine J Perez; Michael R Waterman; Eric Chatelain; Galina I Lepesheva
Journal:  J Biol Chem       Date:  2013-09-18       Impact factor: 5.157

7.  Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae.

Authors:  Laura Friggeri; Tatiana Y Hargrove; Girish Rachakonda; Anna L Blobaum; Paxtyn Fisher; Gabriel Melo de Oliveira; Cristiane França da Silva; Maria de Nazaré C Soeiro; W David Nes; Craig W Lindsley; Fernando Villalta; F Peter Guengerich; Galina I Lepesheva
Journal:  J Med Chem       Date:  2018-11-30       Impact factor: 7.446

8.  A convergent, scalable and stereoselective synthesis of azole CYP51 inhibitors.

Authors:  Galina Lepesheva; Plamen Christov; Gary A Sulikowski; Kwangho Kim
Journal:  Tetrahedron Lett       Date:  2017-09-25       Impact factor: 2.415

9.  Organocatalytic, enantioselective synthesis of VNI: a robust therapeutic development platform for Chagas, a neglected tropical disease.

Authors:  Mark C Dobish; Fernando Villalta; Michael R Waterman; Galina I Lepesheva; Jeffrey N Johnston
Journal:  Org Lett       Date:  2012-12-07       Impact factor: 6.005

10.  In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi.

Authors:  Maria de Nazaré Correia Soeiro; Elen Mello de Souza; Cristiane França da Silva; Denise da Gama Jaen Batista; Marcos Meuser Batista; Beatriz Philot Pavão; Julianna Siciliano Araújo; Claudia Alessandra Fortes Aiub; Patrícia Bernardino da Silva; Jessica Lionel; Constança Britto; Kwangho Kim; Gary Sulikowski; Tatiana Y Hargrove; Michael R Waterman; Galina I Lepesheva
Journal:  Antimicrob Agents Chemother       Date:  2013-06-17       Impact factor: 5.191
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