Phenotypic approaches to lead discovery and optimization of antileishmanial compounds

Leishmaniasis is a spectrum of diseases, caused by species of the protozoan parasite Leishmania,  that afflicts an estimated 12 million individuals worldwide. The disease can present as self-healing but potentially disfiguring cutaneous leishmaniasis; metastatic and highly disfiguring mucocutaneous leishmaniasis; or fatal visceral leishmaniasis, where the parasite targets internal organs such as the liver, spleen, and bone marrow. Leishmaniasis is classified as a major neglected global disease and is considered second in importance only to malaria. Current drugs are poorly efficacious; toxic; subject to resistance; and with the sole exception of miltefosine, parenteral. Because there are only a handful of validated drug targets for Leishmaniasis identifying new targets is of high interest. 

The goal of this project is to identify novel compounds with potential for development into orally bioavailable drugs to treat leishmaniasis. Through a collaboration with the Scott Landfear lab at OHSU, we previously reported a phenotypic screen of ~600,000 compounds to identify compounds with both potent activity against intracellular amastigotes of Leishmania in cultured macrophages, the life cycle stage that causes disease, and low toxicity against mammalian cells.1  On the basis of promising chemical structures, we selected three of those compounds as top ‘hits’ from the phenotypic screen and proposed to interrogate them for development of orally bioavailable lead compounds. Overall, the objective is to identify compounds with potent activity against intracellular amastigotes, the life cycle stage of Leishmania parasites that cause disease, low toxicity against mammalian cells, high oral bioavailability, desirable pharmacokinetic (PK) properties, and with the potential for modification by medicinal chemistry to improve drug-like properties.

References

  1. Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening. Ortiz D, Guiguemde WA, Hammill JT, Carrillo AK, Chen Y, Connelly M, Stalheim K, Elya C, Johnson A, Min J, Shelat A, Smithson DC, Yang L, Zhu F, Guy RK, Landfear SM. PLoS Negl Trop Dis. 2017 Dec 29;11(12):e0006157. doi: 10.1371/journal.pntd.0006157. eCollection 2017 Dec. PMID: 29287089 Free PMC article.
  2. Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P, Alday A, Alemán Resto Y, Alsibaee A, Alzualde A, Andrews KT, Avery SV, Avery VM, Ayong L, Baker M, Baker S, Ben Mamoun C, Bhatia S, Bickle Q, Bounaadja L, Bowling T, Bosch J, Boucher LE, Boyom FF, Brea J, Brennan M, Burton A, Caffrey CR, Camarda G, Carrasquilla M, Carter D, Belen Cassera M, Chih-Chien Cheng K, Chindaudomsate W, Chubb A, Colon BL, Colón-López DD, Corbett Y, Crowther GJ, Cowan N, D’Alessandro S, Le Dang N, Delves M, DeRisi JL, Du AY, Duffy S, Abd El-Salam El-Sayed S, Ferdig MT, Fernández Robledo JA, Fidock DA, Florent I, Fokou PV, Galstian A, Gamo FJ, Gokool S, Gold B, Golub T, Goldgof GM, Guha R, Guiguemde WA, Gural N, Guy RK, Hansen MA, Hanson KK, Hemphill A, Hooft van Huijsduijnen R, Horii T, Horrocks P, Hughes TB, Huston C, Igarashi I, Ingram-Sieber K, Itoe MA, Jadhav A, Naranuntarat Jensen A, Jensen LT, Jiang RH, Kaiser A, Keiser J, Ketas T, Kicka S, Kim S, Kirk K, Kumar VP, Kyle DE, Lafuente MJ, Landfear S, Lee N, Lee S, Lehane AM, Li F, Little D, Liu L, Llinás M, Loza MI, Lubar A, Lucantoni L, Lucet I, Maes L, Mancama D, Mansour NR, March S, McGowan S, Medina Vera I, Meister S, Mercer L, Mestres J, Mfopa AN, Misra RN, Moon S, Moore JP, Morais Rodrigues da Costa F, Müller J, Muriana A, Nakazawa Hewitt S, Nare B, Nathan C, Narraidoo N, Nawaratna S, Ojo KK, Ortiz D, Panic G, Papadatos G, Parapini S, Patra K, Pham N, Prats S, Plouffe DM, Poulsen SA, Pradhan A, Quevedo C, Quinn RJ, Rice CA, Abdo Rizk M, Ruecker A, St Onge R, Salgado Ferreira R, Samra J, Robinett NG, Schlecht U, Schmitt M, Silva Villela F, Silvestrini F, Sinden R, Smith DA, Soldati T, Spitzmüller A, Stamm SM, Sullivan DJ, Sullivan W, Suresh S, Suzuki BM, Suzuki Y, Swamidass SJ, Taramelli D, Tchokouaha LR, Theron A, Thomas D, Tonissen KF, Townson S, Tripathi AK, Trofimov V, Udenze KO, Ullah I, Vallieres C, Vigil E, Vinetz JM, Voong Vinh P, Vu H, Watanabe NA, Weatherby K, White PM, Wilks AF, Winzeler EA, Wojcik E, Wree M, Wu W, Yokoyama N, Zollo PH, Abla N, Blasco B, Burrows J, Laleu B, Leroy D, Spangenberg T, Wells T, Willis PA. PLoS Pathog. 2016 Jul 28;12(7):e1005763. doi: 10.1371/journal.ppat.1005763. eCollection 2016 Jul. PMID: 27467575
  3. Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. Ortiz D, Guiguemde WA, Johnson A, Elya C, Anderson J, Clark J, Connelly M, Yang L, Min J, Sato Y, Guy RK, Landfear SM. PLoS One. 2015 Apr 20;10(4):e0123598. doi: 10.1371/journal.pone.0123598. eCollection 2015. PMID: 25894322
css.php