The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957
Abstract New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible f...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/900b4a91fa834a71a9fd17eeaf2b6009 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:900b4a91fa834a71a9fd17eeaf2b6009 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:900b4a91fa834a71a9fd17eeaf2b60092021-12-02T10:49:29ZThe antimalarial efficacy and mechanism of resistance of the novel chemotype DDD0103495710.1038/s41598-021-81343-z2045-2322https://doaj.org/article/900b4a91fa834a71a9fd17eeaf2b60092021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81343-zhttps://doaj.org/toc/2045-2322Abstract New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957—a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.Celia Miguel-BlancoJames M. MurithiErnest Diez BenaventeFiona AngrisanoKatarzyna A. SalaDonelly A. van SchalkwykManu VanaerschotFrank SchwachMatthew J. FuchterOliver BillkerColin J. SutherlandSusana G. CampinoTaane G. ClarkAndrew M. BlagboroughDavid A. FidockEsperanza HerrerosFrancisco Javier GamoJake BaumMichael J. DelvesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Celia Miguel-Blanco James M. Murithi Ernest Diez Benavente Fiona Angrisano Katarzyna A. Sala Donelly A. van Schalkwyk Manu Vanaerschot Frank Schwach Matthew J. Fuchter Oliver Billker Colin J. Sutherland Susana G. Campino Taane G. Clark Andrew M. Blagborough David A. Fidock Esperanza Herreros Francisco Javier Gamo Jake Baum Michael J. Delves The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| description |
Abstract New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957—a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance. |
| format |
article |
| author |
Celia Miguel-Blanco James M. Murithi Ernest Diez Benavente Fiona Angrisano Katarzyna A. Sala Donelly A. van Schalkwyk Manu Vanaerschot Frank Schwach Matthew J. Fuchter Oliver Billker Colin J. Sutherland Susana G. Campino Taane G. Clark Andrew M. Blagborough David A. Fidock Esperanza Herreros Francisco Javier Gamo Jake Baum Michael J. Delves |
| author_facet |
Celia Miguel-Blanco James M. Murithi Ernest Diez Benavente Fiona Angrisano Katarzyna A. Sala Donelly A. van Schalkwyk Manu Vanaerschot Frank Schwach Matthew J. Fuchter Oliver Billker Colin J. Sutherland Susana G. Campino Taane G. Clark Andrew M. Blagborough David A. Fidock Esperanza Herreros Francisco Javier Gamo Jake Baum Michael J. Delves |
| author_sort |
Celia Miguel-Blanco |
| title |
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| title_short |
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| title_full |
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| title_fullStr |
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| title_full_unstemmed |
The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957 |
| title_sort |
antimalarial efficacy and mechanism of resistance of the novel chemotype ddd01034957 |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/900b4a91fa834a71a9fd17eeaf2b6009 |
| work_keys_str_mv |
AT celiamiguelblanco theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT jamesmmurithi theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT ernestdiezbenavente theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT fionaangrisano theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT katarzynaasala theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT donellyavanschalkwyk theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT manuvanaerschot theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT frankschwach theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT matthewjfuchter theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT oliverbillker theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT colinjsutherland theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT susanagcampino theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT taanegclark theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT andrewmblagborough theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT davidafidock theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT esperanzaherreros theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT franciscojaviergamo theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT jakebaum theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT michaeljdelves theantimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT celiamiguelblanco antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT jamesmmurithi antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT ernestdiezbenavente antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT fionaangrisano antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT katarzynaasala antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT donellyavanschalkwyk antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT manuvanaerschot antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT frankschwach antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT matthewjfuchter antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT oliverbillker antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT colinjsutherland antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT susanagcampino antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT taanegclark antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT andrewmblagborough antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT davidafidock antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT esperanzaherreros antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT franciscojaviergamo antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT jakebaum antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 AT michaeljdelves antimalarialefficacyandmechanismofresistanceofthenovelchemotypeddd01034957 |
| _version_ |
1718396604425175040 |