JairLage

Assistant Adjunct Professor, UCSD

Skaggs School of Pharmacy and Pharmaceutical Sciences

Kinetoplastid and High Throughput Screening Facility Core Director, CDIPD

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Follow me: https://pharmacy.ucsd.edu/faculty/bios/neto.shtml

 I studied biological sciences at the State University of Campinas, Brazil, where I received PhD in genetics and molecular biology, identifying and characterizing telomeric proteins from Leishmania parasites. In 2007, I joined the Institute Pasteur Korea, where I coordinated the development and implementation of high-throughput/high-content screening systems against Leishmania and Trypanosoma cruzi parasites. Working with DNDi we screened libraries for Pfizer, GSK, Sanofi, ANACOR in addition to the IPK library, totaling more than 1 million entries screened.

I joined the CDIPD in 2013 at UCSF as the Kinetoplastid Core Director, leading a team to study the protozoan parasites causing Chagas Disease, Leishmaniasis and Human African Trypanosomiasis with the ultimate goal to discover and develop new chemotherapies and reduce the global burden caused by these diseases. After moving to San Diego in the summer of 2014, in addition to the drug discovery projects leadership, I am responsible for the Screening Facility recently built at the Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD.

Our multidisciplinary research includes molecular and cellular biology, chemistry, pharmacology, computer science and automation. The first step is  development of biological assays for testing efficacy of chemical compounds against the parasites. Then we adapt the assays to automation-friendly microplate format, making it possible to test thousands of candidate compounds in a single experiment. Most of the assays which we develop are image-based. We take pictures of a biological object – for example an infected cell – and program software to analyze and interpret the information contained in each image. This method allows to directly quantify an anti-parasitic activity of each tested compound and is a valuable tool in drug discovery targeting intracellular parasites, such as Trypanosoma cruzi and Leishmania sp. Infection with these parasites causes Chagas Disease or Leishmaniasis, respectively. Once automated assays are statistically validated, we test several thousands of compounds, including synthetic small molecules and natural products from various sources, including academia, public-private partnership research organizations, and pharmaceutical industry. Once hits are identified, medicinal chemists from the collaborating organizations establish structure-activity relationships and optimise hits to improve efficacy and pharmacokinetic profiles. We have also a number of in-house pre-clinical assays including models to address efficacy in vivo.

PUBLICATIONS

Rapid Chagas Disease Drug Target Discovery Using Directed Evolution in Drug-Sensitive Yeast. ACS Chem Biol. 2017 Feb 17;12(2):422-434. doi: 10.1021/acschembio.6b01037. Ottilie S, Goldgof GM, Calvet CM, Jennings GK, LaMonte G, Schenken J, Vigil E, Kumar P, McCall LI, Lopes ES, Gunawan F, Yang J, Suzuki Y, Siqueira-Neto JL, McKerrow JH, Amaro RE, Podust LM, Durrant JD, Winzeler EA.

Location, Location, Location: Five Facts about Tissue Tropism and Pathogenesis. PLoS Pathog. 2016 May;12(5):e1005519. doi: 10.1371/journal.ppat.1005519. No abstract available. McCall LI, Siqueira-Neto JL, McKerrow JH.

Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain. ACS Med Chem Lett. 2016 Jan 14;7(1):77-82. doi: 10.1021/acsmedchemlett.5b00336. Jones BD, Tochowicz A, Tang Y, Cameron MD, McCall LI, Hirata K, Siqueira-Neto JL, Reed SL, McKerrow JH, Roush WR.

Current and Future Chemotherapy for Chagas Disease. Curr Med Chem. 2015;22(37):4293-312. Review. Gaspar L, Moraes CB, Freitas-Junior LH, Ferrari S, Costantino L, Costi MP, Coron RP, Smith TK, Siqueira-Neto JL, McKerrow JH, Cordeiro-da-Silva A.

Genome-Directed Lead Discovery: Biosynthesis, Structure Elucidation, and Biological Evaluation of Two Families of Polyene Macrolactams against Trypanosoma brucei. ACS Chem Biol. 2015 Oct 16;10(10):2373-81. doi: 10.1021/acschembio.5b00308. Epub 2015 Aug 13. Schulze CJ, Donia MS, Siqueira-Neto JL, Ray D, Raskatov JA, Green RE, McKerrow JH, Fischbach MA, Linington RG.

Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery. PLoS Negl Trop Dis. 2015;9(6):e0003878. doi: 10.1371/journal.pntd.0003878. Ekins S, de Siqueira-Neto JL, McCall LI, Sarker M, Yadav M, Ponder EL, Kallel EA, Kellar D, Chen S, Arkin M, Bunin BA, McKerrow JH, Talcott C.

Targeting Ergosterol biosynthesis in Leishmania donovani: essentiality of sterol 14 alpha-demethylase. PLoS Negl Trop Dis. 2015 Mar;9(3):e0003588. doi: 10.1371/journal.pntd.0003588. McCall LI, El Aroussi A, Choi JY, Vieira DF, De Muylder G, Johnston JB, Chen S, Kellar D, Siqueira-Neto JL, Roush WR, Podust LM, McKerrow JH.

Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1. Antimicrob Agents Chemother. 2015 May;59(5):2666-77. doi: 10.1128/AAC.04601-14. Epub 2015 Feb 23. Fonseca NC, da Cruz LF, da Silva Villela F, do Nascimento Pereira GA, de Siqueira-Neto JL, Kellar D, Suzuki BM, Ray D, de Souza TB, Alves RJ, Sales Júnior PA, Romanha AJ, Murta SM, McKerrow JH, Caffrey CR, de Oliveira RB, Ferreira RS.

Proteomic-based approach to gain insight into reprogramming of THP-1 cells exposed to Leishmania donovani over an early temporal window. Infect Immun. 2015 May;83(5):1853-68. doi: 10.1128/IAI.02833-14. Epub 2015 Feb 17. Singh AK, Pandey RK, Siqueira-Neto JL, Kwon YJ, Freitas-Junior LH, Shaha C, Madhubala R.

RPA-1 from Leishmania amazonensis (LaRPA-1) structurally differs from other eukaryote RPA-1 and interacts with telomeric DNA via its N-terminal OB-fold domain. FEBS Lett. 2014 Dec 20;588(24):4740-8. doi: 10.1016/j.febslet.2014.11.005. Epub 2014 Nov 15. Pavani RS, Fernandes C, Perez AM, Vasconcelos EJ, Siqueira-Neto JL, Fontes MR, Cano MI.

Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51. J Med Chem. 2014 Dec 11;57(23):10162-75. doi: 10.1021/jm501568b. Epub 2014 Nov 25. Vieira DF, Choi JY, Calvet CM, Siqueira-Neto JL, Johnston JB, Kellar D, Gut J, Cameron MD, McKerrow JH, Roush WR, Podust LM.

Drug discovery for human African trypanosomiasis: identification of novel scaffolds by the newly developed HTS SYBR Green assay for Trypanosoma brucei. J Biomol Screen. 2015 Jan;20(1):70-81. doi: 10.1177/1087057114556236. Epub 2014 Oct 23. Faria J, Moraes CB, Song R, Pascoalino BS, Lee N, Siqueira-Neto JL, Cruz DJ, Parkinson T, Ioset JR, Cordeiro-da-Silva A, Freitas-Junior LH.

Lead identification to clinical candidate selection: drugs for Chagas disease. J Biomol Screen. 2015 Jan;20(1):101-11. doi: 10.1177/1087057114553103. Epub 2014 Oct 3. Neitz RJ, Chen S, Supek F, Yeh V, Kellar D, Gut J, Bryant C, Gallardo-Godoy A, Molteni V, Roach SL, Chatterjee AK, Robertson S, Renslo AR, Arkin M, Glynne R, McKerrow J, Siqueira-Neto JL.

4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J Med Chem. 2014 Aug 28;57(16):6989-7005. doi: 10.1021/jm500448u. Epub 2014 Aug 19. Calvet CM, Vieira DF, Choi JY, Kellar D, Cameron MD, Siqueira-Neto JL, Gut J, Johnston JB, Lin L, Khan S, McKerrow JH, Roush WR, Podust LM.

Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a]benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi. Eur J Med Chem. 2014 Sep 12;84:395-403. doi: 10.1016/j.ejmech.2014.07.038. Epub 2014 Jul 11. Oh S, Kim S, Kong S, Yang G, Lee N, Han D, Goo J, Siqueira-Neto JL, Freitas-Junior LH, Song R.

Diversity-oriented synthesis yields a new drug lead for treatment of Chagas disease. ACS Med Chem Lett. 2014 Feb 13;5(2):149-53. doi: 10.1021/ml400403u. Dandapani S, Germain AR, Jewett I, le Quement S, Marie JC, Muncipinto G, Duvall JR, Carmody LC, Perez JR, Engel JC, Gut J, Kellar D, Siqueira-Neto JL, McKerrow JH, Kaiser M, Rodriguez A, Palmer MA, Foley M, Schreiber SL, Munoz B.

An image-based algorithm for precise and accurate high throughput assessment of drug activity against the human parasite Trypanosoma cruzi. PLoS One. 2014;9(2):e87188. doi: 10.1371/journal.pone.0087188. Moon S, Siqueira-Neto JL, Moraes CB, Yang G, Kang M, Freitas-Junior LH, Hansen MA.

Visceral leishmaniasis treatment: What do we have, what do we need and how to deliver it? Int J Parasitol Drugs Drug Resist. 2012 Dec;2:11-9. doi: 10.1016/j.ijpddr.2012.01.003. Review. Freitas-Junior LH, Chatelain E, Kim HA, Siqueira-Neto JL.

An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. PLoS Negl Trop Dis. 2012;6(6):e1671. doi: 10.1371/journal.pntd.0001671. Epub 2012 Jun 12. Siqueira-Neto JL, Moon S, Jang J, Yang G, Lee C, Moon HK, Chatelain E, Genovesio A, Cechetto J, Freitas-Junior LH.

The Leishmania amazonensis TRF (TTAGGG repeat-binding factor) homologue binds and co-localizes with telomeres. BMC Microbiol. 2010 May 7;10:136. doi: 10.1186/1471-2180-10-136. da Silva MS, Perez AM, da Silveira Rde C, de Moraes CE, Siqueira-Neto JL, Freitas Lde H Jr, Cano MI.

Antileishmanial high-throughput drug screening reveals drug candidates with new scaffolds. PLoS Negl Trop Dis. 2010 May 4;4(5):e675. doi: 10.1371/journal.pntd.0000675. Siqueira-Neto JL, Song OR, Oh H, Sohn JH, Yang G, Nam J, Jang J, Cechetto J, Lee CB, Moon S, Genovesio A, Chatelain E, Christophe T, Freitas-Junior LH.

Automated nuclear analysis of Leishmania major telomeric clusters reveals changes in their organization during the parasite's life cycle. PLoS One. 2008 Jun 11;3(6):e2313. doi: 10.1371/journal.pone.0002313. Dossin Fde M, Dufour A, Dusch E, Siqueira-Neto JL, Moraes CB, Yang GS, Cano MI, Genovesio A, Freitas-Junior LH.

LaTBP1: a Leishmania amazonensis DNA-binding protein that associates in vivo with telomeres and GT-rich DNA using a Myb-like domain. Arch Biochem Biophys. 2007 Sep 15;465(2):399-409. Epub 2007 Jun 29. Lira CB, de Siqueira-Neto JL, Khater L, Cagliari TC, Peroni LA, dos Reis JR, Ramos CH, Cano MI.

Telomere biology of trypanosomatids: beginning to answer some questions. Trends Parasitol. 2007 Aug;23(8):357-62. Epub 2007 Jun 18. Review. Lira CB, Giardini MA, Siqueira-Neto JL, Conte FF, Cano MI.

LaRbp38: a Leishmania amazonensis protein that binds nuclear and kinetoplast DNAs. Biochem Biophys Res Commun. 2007 Jul 6;358(3):854-60. Epub 2007 May 8. Lira CB, Siqueira-Neto JL, Giardini MA, Winck FV, Ramos CH, Cano MI.

Leishmania replication protein A-1 binds in vivo single-stranded telomeric DNA. Biochem Biophys Res Commun. 2007 Jun 29;358(2):417-23. Epub 2007 May 4. Siqueira-Neto JL, Lira CB, Giardini MA, Khater L, Perez AM, Peroni LA, dos Reis JR, Freitas-Junior LH, Ramos CH, Cano MI.

The putative telomerase reverse transcriptase component of Leishmania amazonensis: gene cloning and characterization. Parasitol Res. 2006 Apr;98(5):447-54. Epub 2006 Jan 14. Giardini MA, Lira CB, Conte FF, Camillo LR, de Siqueira-Neto JL, Ramos CH, Cano MI.