Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model
Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.
| Errataetall: |
ErratumIn: J Med Chem. 2021 Dec 23;64(24):18236. - PMID 34854304 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 62(2019), 6 vom: 28. März, Seite 3021-3035 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Giordani, Federica [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
673LC5J4LQ |
|---|
| Anmerkungen: |
Date Completed 03.03.2020 Date Revised 02.12.2021 published: Print-Electronic ErratumIn: J Med Chem. 2021 Dec 23;64(24):18236. - PMID 34854304 Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.8b01847 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM293886660 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM293886660 | ||
| 003 | DE-627 | ||
| 005 | 20231225080305.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.8b01847 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0979.xml |
| 035 | |a (DE-627)NLM293886660 | ||
| 035 | |a (NLM)30763102 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Giordani, Federica |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.03.2020 | ||
| 500 | |a Date Revised 02.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: J Med Chem. 2021 Dec 23;64(24):18236. - PMID 34854304 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT: Trypanosoma congolense, and Trypanosoma vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative by using two applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 650 | 7 | |a Pentamidine |2 NLM | |
| 650 | 7 | |a 673LC5J4LQ |2 NLM | |
| 700 | 1 | |a Khalaf, Abedawn I |e verfasserin |4 aut | |
| 700 | 1 | |a Gillingwater, Kirsten |e verfasserin |4 aut | |
| 700 | 1 | |a Munday, Jane C |e verfasserin |4 aut | |
| 700 | 1 | |a de Koning, Harry P |e verfasserin |4 aut | |
| 700 | 1 | |a Suckling, Colin J |e verfasserin |4 aut | |
| 700 | 1 | |a Barrett, Michael P |e verfasserin |4 aut | |
| 700 | 1 | |a Scott, Fraser J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 62(2019), 6 vom: 28. März, Seite 3021-3035 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:62 |g year:2019 |g number:6 |g day:28 |g month:03 |g pages:3021-3035 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.8b01847 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 62 |j 2019 |e 6 |b 28 |c 03 |h 3021-3035 | ||