Author:
- Introduction
- Drug Discovery Algorithm
- In vitro evaluation of potential anti-CL agents.
- In vivo evaluation of potential oral agents for CL agents.
- Tier 1a: in vitro mouse suppression test.
- Tiers 1b and 2: mouse treatment test.
- Tier 1b: in vivo mouse treatment test with intraperitoneal drug administration.
- Tier 2: mouse treatment test with oral drug administration.
- Tier 3: in vivo hamster treatment test.
- Transition to drug development.
- Discussion
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Desjeux P, 2001. The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 95: 239–243.
-
2.
World Health Organization, 2010. Control of the leishmaniases. World Health Organ Tech Rep Ser 949: 1–186.
-
3.
Gonzalez U, Pinart M, Reveiz L, Rengifo-Pardo M, Tweed J, Macaya A, Alvar J, 2010. Designing and reporting clinical trials on treatments for cutaneous leishmaniasis. Clin Infect Dis 51: 409–419.
-
4.
Sharlow ER, Grögl M, Johnson J, Lazo JS, 2010. Anti-leishmanial drug discovery: rising to the challenges of a highly neglected disease. Mol Interv 10: 72–75.
-
5.
Ben Salah A, Buffet PA, Morizot G, Ben Massoud N, Zâatour A, Ben Alaya N, Haj Hamida NB, El Ahmadi Z, Downs MT, Smith PL, Dellagi K, Grögl M, 2009. WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a Phase 2, randomized, double blind, placebo controlled study. PLoS Negl Trop Dis 3: e432.
-
6.
Sharlow ER, Close D, Shun T, Leimgruber S, Reed R, Mustata G, Wipf P, Johnson J, O'Neil M, Grögl M, Magill AJ, Lazo JS, 2009. Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. PLoS Negl Trop Dis 3: e540.
-
7.
Sharlow ER, Leimgruber S, Yellow-Duke A, Barrett R, Wang QJ, Lazo JS, 2008. Development, validation and implementation of immobilized metal affinity for phosphochemicals (IMAP)-based high-throughput screening assays for low-molecular-weight compound libraries. Nat Protoc 3: 1350–1363.
-
8.
De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH, 2011. A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis 5: e1253.
-
9.
Zhu X, Pandharkar T, Werbovetz K, 2012. Identification of new antileishmanial leads from hits obtained by high-throughput screening. Antimicrob Agents Chemother 56: 1182–1189.
-
10.
Sakthianandeswaren A, Foote SJ, Handman E, 2009. The role of host genetics in leishmaniasis. Trends Parasitol 25: 383–391.
-
11.
Hanson WL, Chapman WL, Waits VL, Lovelace JK, 1991. Development of Leishmania (Vianna) panamensis lesions and relationship of numbers of amastigotes to lesion areas on antimony-treated and untreated hamsters. J Parasitol 77: 780–783.
-
12.
Mortelmans K, Zeiger E, 2000. The Ames Salmonella/M microsome mutagenicity assay. Mutat Res 455: 29–60.
-
13.
Fenech M, 2000. The in vitro micronucleus technique. Mutat Res 455: 81–95.
-
14.
Sanguinetti M, Mitcheson J, 2005. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci 26: 119–124.
-
15.
Serrano-MartÃn X, Payares G, De Lucca M, Martinez JC, Mendoza-León A, Benaim G, 2009. Amiodarone and miltefosine act synergistically against Leishmania mexicana and can induce parasitological cure in a murine model of cutaneous leishmaniasis. Antimicrob Agents Chemother 53: 5108–5113.
-
16.
Silva-Almeida M, Carvalho LO, Abreu-Silva AL, d'Escoffier LN, Calabrese KS, 2010. Leishmania (Leishmania) amazonensis infection: muscular involvement in BALB/c and C3H.HeN mice. Exp Parasitol 124: 315–318.
-
17.
Castilho TM, Goldsmith-Pestana K, Lozano C, Valderrama L, Saravia NG, McMahon-Pratt D, 2010. Murine model of chronic L. (Viannia) panamensis infection: role of IL-13 in disease. Eur J Immunol 40: 2816–2829.
-
18.
Tonui W, Titus RG, 2007. Cross-protection against Leishmania donovani but not L. braziliensis caused by vaccination with L. major soluble promastigote exogenous antigens in BALB/C mice. Am J Trop Med Hyg 76: 579–584.
-
19.
Morais-Teixeira E, Carvalho AS, Costa J, Duarte SL, Mendonça JS, Boechat N, Rabello A, 2008. In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L. (L.) chagasi and L. (Viannia) braziliensis. Mem Inst Oswaldo Cruz 103: 358–362.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 2299 | 2114 | 64 |
| Full Text Views | 1167 | 11 | 4 |
| PDF Downloads | 141 | 6 | 2 |
Drug Discovery Algorithm for Cutaneous Leishmaniasis
Max Grogl
Max Grogl
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Mark Hickman
Mark Hickman
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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William Ellis
William Ellis
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Thomas Hudson
Thomas Hudson
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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John S. Lazo
John S. Lazo
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Elizabeth R. Sharlow
Elizabeth R. Sharlow
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Jacob Johnson
Jacob Johnson
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Jonathan Berman
Jonathan Berman
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Richard J. Sciotti
Richard J. Sciotti
Division Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; Drug Discovery Institute and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, Virginia
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Cutaneous leishmaniasis is clinically widespread but lacks treatments that are effective and well tolerated. Because all present drugs have been grandfathered into clinical use, there are no examples of a pre-clinical product evaluation scheme that lead to new candidates for formal development. To provide oral agents for development targeting cutaneous leishmaniasis, we have implemented a discovery scheme that incorporates in vitro and in vivo testing of efficacy, toxicity, and pharmacokinetics/metabolism. Particular emphasis is placed on in vivo testing, progression from higher-throughput models to those with most clinical relevance, and efficient use of resources.
Author Notes
Authors' addresses: Max Grogl, Mark Hickman, William Ellis, Thomas Hudson, Jacob Johnson, Jonathan Berman, and Richard J. Sciotti, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, E-mails: max.grogl1@us.army.mil, mark.r.hickman@us.army.mil, bill.ellis@us.army.mil, thomas.hudson@us.army.mil, jjohnson@wrp-ksm.org, jbe9320457@aol.com, and richard.sciotti@us.army.mil. John S. Lazo, Department of Pharmacology and Chemistry, University of Virginia, Charlottesville, VA, E-mail: jsl8f@hscmail.mcc.virginia.edu. Elizabeth R. Sharlow, Department of Pharmacology, University of Virginia, Charlottesville, VA, E-mail: ers7g@virginia.edu.
- Introduction
- Drug Discovery Algorithm
- In vitro evaluation of potential anti-CL agents.
- In vivo evaluation of potential oral agents for CL agents.
- Tier 1a: in vitro mouse suppression test.
- Tiers 1b and 2: mouse treatment test.
- Tier 1b: in vivo mouse treatment test with intraperitoneal drug administration.
- Tier 2: mouse treatment test with oral drug administration.
- Tier 3: in vivo hamster treatment test.
- Transition to drug development.
- Discussion
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1.
Desjeux P, 2001. The increase in risk factors for leishmaniasis worldwide. Trans R Soc Trop Med Hyg 95: 239–243.
-
2.
World Health Organization, 2010. Control of the leishmaniases. World Health Organ Tech Rep Ser 949: 1–186.
-
3.
Gonzalez U, Pinart M, Reveiz L, Rengifo-Pardo M, Tweed J, Macaya A, Alvar J, 2010. Designing and reporting clinical trials on treatments for cutaneous leishmaniasis. Clin Infect Dis 51: 409–419.
-
4.
Sharlow ER, Grögl M, Johnson J, Lazo JS, 2010. Anti-leishmanial drug discovery: rising to the challenges of a highly neglected disease. Mol Interv 10: 72–75.
-
5.
Ben Salah A, Buffet PA, Morizot G, Ben Massoud N, Zâatour A, Ben Alaya N, Haj Hamida NB, El Ahmadi Z, Downs MT, Smith PL, Dellagi K, Grögl M, 2009. WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a Phase 2, randomized, double blind, placebo controlled study. PLoS Negl Trop Dis 3: e432.
-
6.
Sharlow ER, Close D, Shun T, Leimgruber S, Reed R, Mustata G, Wipf P, Johnson J, O'Neil M, Grögl M, Magill AJ, Lazo JS, 2009. Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. PLoS Negl Trop Dis 3: e540.
-
7.
Sharlow ER, Leimgruber S, Yellow-Duke A, Barrett R, Wang QJ, Lazo JS, 2008. Development, validation and implementation of immobilized metal affinity for phosphochemicals (IMAP)-based high-throughput screening assays for low-molecular-weight compound libraries. Nat Protoc 3: 1350–1363.
-
8.
De Muylder G, Ang KK, Chen S, Arkin MR, Engel JC, McKerrow JH, 2011. A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. PLoS Negl Trop Dis 5: e1253.
-
9.
Zhu X, Pandharkar T, Werbovetz K, 2012. Identification of new antileishmanial leads from hits obtained by high-throughput screening. Antimicrob Agents Chemother 56: 1182–1189.
-
10.
Sakthianandeswaren A, Foote SJ, Handman E, 2009. The role of host genetics in leishmaniasis. Trends Parasitol 25: 383–391.
-
11.
Hanson WL, Chapman WL, Waits VL, Lovelace JK, 1991. Development of Leishmania (Vianna) panamensis lesions and relationship of numbers of amastigotes to lesion areas on antimony-treated and untreated hamsters. J Parasitol 77: 780–783.
-
12.
Mortelmans K, Zeiger E, 2000. The Ames Salmonella/M microsome mutagenicity assay. Mutat Res 455: 29–60.
-
13.
Fenech M, 2000. The in vitro micronucleus technique. Mutat Res 455: 81–95.
-
14.
Sanguinetti M, Mitcheson J, 2005. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol Sci 26: 119–124.
-
15.
Serrano-MartÃn X, Payares G, De Lucca M, Martinez JC, Mendoza-León A, Benaim G, 2009. Amiodarone and miltefosine act synergistically against Leishmania mexicana and can induce parasitological cure in a murine model of cutaneous leishmaniasis. Antimicrob Agents Chemother 53: 5108–5113.
-
16.
Silva-Almeida M, Carvalho LO, Abreu-Silva AL, d'Escoffier LN, Calabrese KS, 2010. Leishmania (Leishmania) amazonensis infection: muscular involvement in BALB/c and C3H.HeN mice. Exp Parasitol 124: 315–318.
-
17.
Castilho TM, Goldsmith-Pestana K, Lozano C, Valderrama L, Saravia NG, McMahon-Pratt D, 2010. Murine model of chronic L. (Viannia) panamensis infection: role of IL-13 in disease. Eur J Immunol 40: 2816–2829.
-
18.
Tonui W, Titus RG, 2007. Cross-protection against Leishmania donovani but not L. braziliensis caused by vaccination with L. major soluble promastigote exogenous antigens in BALB/C mice. Am J Trop Med Hyg 76: 579–584.
-
19.
Morais-Teixeira E, Carvalho AS, Costa J, Duarte SL, Mendonça JS, Boechat N, Rabello A, 2008. In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L. (L.) chagasi and L. (Viannia) braziliensis. Mem Inst Oswaldo Cruz 103: 358–362.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 2299 | 2114 | 64 |
| Full Text Views | 1167 | 11 | 4 |
| PDF Downloads | 141 | 6 | 2 |