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Identification of cysteine protease inhibitors as new drug leads against Naegleria fowleri.
Exp Parasitol. 2018 May; 188:36-41.EP

Abstract

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. PAM occurs principally in healthy children of less than 13 years old with a history of recent exposure to warm fresh water. While as yet not a reportable disease, the Centers for Disease Control and Prevention (CDC) documents a total of 143 cases in the United States. Only four patients have survived. Infection results from water containing N. fowleri entering the nose, followed by migration of the amebae to the brain. Within the brain, N. fowleri infection results in extensive necrosis, leading to death in 3-7 days. Mortality among patients with PAM is greater than 95%. The drugs of choice in treating PAM are the antifungal amphotericin B, and the antileishmanial, miltefosine. However neither drug is FDA-approved for this indication and the use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with amphotericin B have survived PAM. Therefore, development of new, safe and effective drugs is a critical unmet need to avert future deaths of children. The molecular mechanisms underlying the pathogenesis of PAM are poorly understood but it is known that cysteine proteases of N. fowleri play a role in the progression of PAM. We therefore assessed the in vitro activity of the synthetic vinyl sulfone cysteine protease inhibitor, K11777, and 33 analogs with valine, phenylalanine or pyridylalanine at P2 position, against cysteine protease activity in the lysate of N. fowleri. Inhibitors with phenylalanine or pyridylalanine at P2 position were particularly effective in inhibiting the cysteine protease activity of N. fowleri cell lysate with IC50 ranging between 3 nM and 6.6 μM. Three of the 34 inhibitors also showed inhibitory activity against N. fowleri in a cell viability assay and were 1.6- to 2.5-fold more potent than the standard of care drug miltefosine. Our study provides the first evidence of the activity of synthetic, small molecule cysteine protease inhibitors against N. fowleri.

Authors+Show Affiliations

Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC0755, La Jolla, CA 92093-0755, USA.The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A2, Jupiter, FL 33458, USA.The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A2, Jupiter, FL 33458, USA.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC0755, La Jolla, CA 92093-0755, USA.The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A2, Jupiter, FL 33458, USA.Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC0755, La Jolla, CA 92093-0755, USA. Electronic address: adebnath@ucsd.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29551628

Citation

Zyserman, Ingrid, et al. "Identification of Cysteine Protease Inhibitors as New Drug Leads Against Naegleria Fowleri." Experimental Parasitology, vol. 188, 2018, pp. 36-41.
Zyserman I, Mondal D, Sarabia F, et al. Identification of cysteine protease inhibitors as new drug leads against Naegleria fowleri. Exp Parasitol. 2018;188:36-41.
Zyserman, I., Mondal, D., Sarabia, F., McKerrow, J. H., Roush, W. R., & Debnath, A. (2018). Identification of cysteine protease inhibitors as new drug leads against Naegleria fowleri. Experimental Parasitology, 188, 36-41. https://doi.org/10.1016/j.exppara.2018.03.010
Zyserman I, et al. Identification of Cysteine Protease Inhibitors as New Drug Leads Against Naegleria Fowleri. Exp Parasitol. 2018;188:36-41. PubMed PMID: 29551628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of cysteine protease inhibitors as new drug leads against Naegleria fowleri. AU - Zyserman,Ingrid, AU - Mondal,Deboprosad, AU - Sarabia,Francisco, AU - McKerrow,James H, AU - Roush,William R, AU - Debnath,Anjan, Y1 - 2018/03/15/ PY - 2018/02/04/received PY - 2018/03/13/accepted PY - 2018/3/20/pubmed PY - 2018/5/5/medline PY - 2018/3/20/entrez KW - Drug discovery KW - Drug leads KW - Inhibitors KW - Naegleria fowleri KW - Primary amebic meningoencephalitis KW - cysteine protease SP - 36 EP - 41 JF - Experimental parasitology JO - Exp. Parasitol. VL - 188 N2 - Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. PAM occurs principally in healthy children of less than 13 years old with a history of recent exposure to warm fresh water. While as yet not a reportable disease, the Centers for Disease Control and Prevention (CDC) documents a total of 143 cases in the United States. Only four patients have survived. Infection results from water containing N. fowleri entering the nose, followed by migration of the amebae to the brain. Within the brain, N. fowleri infection results in extensive necrosis, leading to death in 3-7 days. Mortality among patients with PAM is greater than 95%. The drugs of choice in treating PAM are the antifungal amphotericin B, and the antileishmanial, miltefosine. However neither drug is FDA-approved for this indication and the use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with amphotericin B have survived PAM. Therefore, development of new, safe and effective drugs is a critical unmet need to avert future deaths of children. The molecular mechanisms underlying the pathogenesis of PAM are poorly understood but it is known that cysteine proteases of N. fowleri play a role in the progression of PAM. We therefore assessed the in vitro activity of the synthetic vinyl sulfone cysteine protease inhibitor, K11777, and 33 analogs with valine, phenylalanine or pyridylalanine at P2 position, against cysteine protease activity in the lysate of N. fowleri. Inhibitors with phenylalanine or pyridylalanine at P2 position were particularly effective in inhibiting the cysteine protease activity of N. fowleri cell lysate with IC50 ranging between 3 nM and 6.6 μM. Three of the 34 inhibitors also showed inhibitory activity against N. fowleri in a cell viability assay and were 1.6- to 2.5-fold more potent than the standard of care drug miltefosine. Our study provides the first evidence of the activity of synthetic, small molecule cysteine protease inhibitors against N. fowleri. SN - 1090-2449 UR - https://www.unboundmedicine.com/medline/citation/29551628/Identification_of_cysteine_protease_inhibitors_as_new_drug_leads_against_Naegleria_fowleri_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4894(18)30060-2 DB - PRIME DP - Unbound Medicine ER -