Deciphering Chemical Rules for Drug Penetration into Strongyloides
<b>Background:</b> Strongyloidiasis, a parasitic infection, presents a significant public health challenge in tropical regions due to the limited repertoire of effective treatments. The screening of chemical libraries against the therapeutically relevant third-stage larvae (L3) of the mo...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-09-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/16/9/1224 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850259864685641728 |
|---|---|
| author | Miguel Marín Javier Sánchez-Montejo Sergio Ramos Antonio Muro Julio López-Abán Rafael Peláez |
| author_facet | Miguel Marín Javier Sánchez-Montejo Sergio Ramos Antonio Muro Julio López-Abán Rafael Peláez |
| author_sort | Miguel Marín |
| collection | DOAJ |
| description | <b>Background:</b> Strongyloidiasis, a parasitic infection, presents a significant public health challenge in tropical regions due to the limited repertoire of effective treatments. The screening of chemical libraries against the therapeutically relevant third-stage larvae (L3) of the model parasite <i>Strongyloides venezuelensis</i> yielded meager success rates. This situation is reminiscent of Gram-negative bacteria, where drug entry is a limiting factor. <b>Methods:</b> Here, we set out to determine whether similar barriers are in place and establish whether structural and property requirements exist for anti-strongyloides drug discovery. We focused on dyes as their uptake and effects on viability can be independently assessed in the multicellular parasite, thus providing a means to study the possibility of similar entry rules. We tested different dyes in in vitro assays on L3s. <b>Results:</b> We found that staining was necessary to reduce parasite viability, with some dyes achieving anti-strongyloides effects at concentrations similar to those of the reference drug, ivermectin (IV). Some dyes also showed activity against female adults at concentrations well below that of ivermectin. Unfortunately, the most potent dye, Methylene Blue, was unable to prevent the infection in a preliminary in vivo mouse model assay, presumably due to fast dye clearance. Structural analysis showed that positive charges facilitated the access of the compounds to the L3 tissue, thus providing a structural tool for the introduction of activity. For female adults, low globularity is additionally required. As a proof of concept, we added a positive charge to an inactive compound of one of our chemical libraries and re-determined the activity. <b>Conclusions:</b> These findings allow us to establish structural rules for parasite entry that could be of interest for future drug screening or drug development campaigns. These rules might also be applicable to other related parasites. |
| format | Article |
| id | doaj-art-92c88bba84964ba895ca2f9d4605ea58 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-92c88bba84964ba895ca2f9d4605ea582025-08-20T01:55:46ZengMDPI AGPharmaceutics1999-49232024-09-01169122410.3390/pharmaceutics16091224Deciphering Chemical Rules for Drug Penetration into StrongyloidesMiguel Marín0Javier Sánchez-Montejo1Sergio Ramos2Antonio Muro3Julio López-Abán4Rafael Peláez5Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, SpainInfectious and Tropical Diseases Research Group (e-INTRO), Biomedical Research Institute of Salamanca Research Centre for Tropical Diseases at the University of Salamanca (IBSAL-CIETUS), E-37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, SpainInfectious and Tropical Diseases Research Group (e-INTRO), Biomedical Research Institute of Salamanca Research Centre for Tropical Diseases at the University of Salamanca (IBSAL-CIETUS), E-37007 Salamanca, SpainInfectious and Tropical Diseases Research Group (e-INTRO), Biomedical Research Institute of Salamanca Research Centre for Tropical Diseases at the University of Salamanca (IBSAL-CIETUS), E-37007 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain<b>Background:</b> Strongyloidiasis, a parasitic infection, presents a significant public health challenge in tropical regions due to the limited repertoire of effective treatments. The screening of chemical libraries against the therapeutically relevant third-stage larvae (L3) of the model parasite <i>Strongyloides venezuelensis</i> yielded meager success rates. This situation is reminiscent of Gram-negative bacteria, where drug entry is a limiting factor. <b>Methods:</b> Here, we set out to determine whether similar barriers are in place and establish whether structural and property requirements exist for anti-strongyloides drug discovery. We focused on dyes as their uptake and effects on viability can be independently assessed in the multicellular parasite, thus providing a means to study the possibility of similar entry rules. We tested different dyes in in vitro assays on L3s. <b>Results:</b> We found that staining was necessary to reduce parasite viability, with some dyes achieving anti-strongyloides effects at concentrations similar to those of the reference drug, ivermectin (IV). Some dyes also showed activity against female adults at concentrations well below that of ivermectin. Unfortunately, the most potent dye, Methylene Blue, was unable to prevent the infection in a preliminary in vivo mouse model assay, presumably due to fast dye clearance. Structural analysis showed that positive charges facilitated the access of the compounds to the L3 tissue, thus providing a structural tool for the introduction of activity. For female adults, low globularity is additionally required. As a proof of concept, we added a positive charge to an inactive compound of one of our chemical libraries and re-determined the activity. <b>Conclusions:</b> These findings allow us to establish structural rules for parasite entry that could be of interest for future drug screening or drug development campaigns. These rules might also be applicable to other related parasites.https://www.mdpi.com/1999-4923/16/9/1224<i>Strongyloides venezuelensis</i>dyesnematocidal activitystructure–activity relationshipsentry rules |
| spellingShingle | Miguel Marín Javier Sánchez-Montejo Sergio Ramos Antonio Muro Julio López-Abán Rafael Peláez Deciphering Chemical Rules for Drug Penetration into Strongyloides Pharmaceutics <i>Strongyloides venezuelensis</i> dyes nematocidal activity structure–activity relationships entry rules |
| title | Deciphering Chemical Rules for Drug Penetration into Strongyloides |
| title_full | Deciphering Chemical Rules for Drug Penetration into Strongyloides |
| title_fullStr | Deciphering Chemical Rules for Drug Penetration into Strongyloides |
| title_full_unstemmed | Deciphering Chemical Rules for Drug Penetration into Strongyloides |
| title_short | Deciphering Chemical Rules for Drug Penetration into Strongyloides |
| title_sort | deciphering chemical rules for drug penetration into strongyloides |
| topic | <i>Strongyloides venezuelensis</i> dyes nematocidal activity structure–activity relationships entry rules |
| url | https://www.mdpi.com/1999-4923/16/9/1224 |
| work_keys_str_mv | AT miguelmarin decipheringchemicalrulesfordrugpenetrationintostrongyloides AT javiersanchezmontejo decipheringchemicalrulesfordrugpenetrationintostrongyloides AT sergioramos decipheringchemicalrulesfordrugpenetrationintostrongyloides AT antoniomuro decipheringchemicalrulesfordrugpenetrationintostrongyloides AT juliolopezaban decipheringchemicalrulesfordrugpenetrationintostrongyloides AT rafaelpelaez decipheringchemicalrulesfordrugpenetrationintostrongyloides |