TY - JOUR
T1 - In vitro and in vivo characterization of potent antileishmanial methionine aminopeptidase 1 inhibitors
AU - Rodriguez, Felipe
AU - John, Sarah F.
AU - Iniguez, Eva
AU - Montalvo, Sebastian
AU - Michael, Karina
AU - White, Lyndsey
AU - Liang, Dong
AU - Olaleye, Omonike A.
AU - Maldonado, Rosa A.
N1 - Funding Information:
Funding was provided by NIH/ARRA-RTRN grant number U54RR022762 (to R.A.M.), NIGMS/NIH/BUILD grant numbers RL5GM118969, TL4GM118971, and UL1GM118970 (to R.A.M. and O.A.O.), NIH/MARC grant number 2T34GM008048 (to S.M.), and NIH/NIGMS/ RISE grant number R25GM069621-11 (to F.R., E.I., and S.M.).
Funding Information:
We are grateful to the following UTEP/BBRC Core Facilities: Biomolecule Analysis (BACF), Cytometry, Screening and Imaging (CSI), and Genomic Analysis (GACF) (supported by NIH/NIMHD grant number 2G12MD007592-21) and Laboratory Animal Resources Center (LARC) at UTEP. This collaborative work was supported in part by Texas Southern University Research Center for Minority Institutions NIH/NIMHD grant number 5G12MD007605.
Publisher Copyright:
© 2020 American Society for Microbiology. All Rights Reserved.
PY - 2020/5/21
Y1 - 2020/5/21
N2 - Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.
AB - Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.
KW - Antiparasitic agents
KW - Cutaneous leishmaniasis
KW - Drug discovery
KW - Leishmania major
KW - Methionine aminopeptidase 1
KW - Molecular parasitology
KW - Murine model of cutaneous leishmaniasis
KW - Parasitology
KW - Target validation
UR - http://www.scopus.com/inward/record.url?scp=85085264234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085264234&partnerID=8YFLogxK
U2 - 10.1128/AAC.01422-19
DO - 10.1128/AAC.01422-19
M3 - Article
C2 - 32179532
AN - SCOPUS:85085264234
SN - 0066-4804
VL - 64
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 6
M1 - e01422-19
ER -