Abstract
Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
| Original language | English |
|---|---|
| Pages (from-to) | 5060-5067 |
| Number of pages | 8 |
| Journal | Antimicrobial Agents and Chemotherapy |
| Volume | 58 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2014 |
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KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission. / Kuhen, Kelli L.; Chatterjee, Arnab K.; Rottmann, Matthias; Gagaring, Kerstin; Borboa, Rachel; Buenviaje, Jennifer; Chen, Zhong; Francek, Carolyn; Wu, Tao; Nagle, Advait; Barnes, S. Whitney; Plouffe, David; Lee, Marcus C.S.; Fidock, David A.; Graumans, Wouter; Van De Vegte-Bolmer, Marga; Van Gemert, Geert J.; Wirjanata, Grennady; Sebayang, Boni; Marfurt, Jutta; Russell, Bruce; Suwanarusk, Rossarin; Price, Ric N.; Nosten, Francois; Tungtaeng, Anchalee; Gettayacamin, Montip; Sattabongkot, Jetsumon; Taylor, Jennifer; Walker, John R.; Tully, David; Patra, Kailash P.; Flannery, Erika L.; Vinetz, Joseph M.; Renia, Laurent; Sauerwein, Robert W.; Winzeler, Elizabeth A.; Glynne, Richard J.; Diagana, Thierry T.
In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 9, 2014, p. 5060-5067.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission
AU - Kuhen, Kelli L.
AU - Chatterjee, Arnab K.
AU - Rottmann, Matthias
AU - Gagaring, Kerstin
AU - Borboa, Rachel
AU - Buenviaje, Jennifer
AU - Chen, Zhong
AU - Francek, Carolyn
AU - Wu, Tao
AU - Nagle, Advait
AU - Barnes, S. Whitney
AU - Plouffe, David
AU - Lee, Marcus C.S.
AU - Fidock, David A.
AU - Graumans, Wouter
AU - Van De Vegte-Bolmer, Marga
AU - Van Gemert, Geert J.
AU - Wirjanata, Grennady
AU - Sebayang, Boni
AU - Marfurt, Jutta
AU - Russell, Bruce
AU - Suwanarusk, Rossarin
AU - Price, Ric N.
AU - Nosten, Francois
AU - Tungtaeng, Anchalee
AU - Gettayacamin, Montip
AU - Sattabongkot, Jetsumon
AU - Taylor, Jennifer
AU - Walker, John R.
AU - Tully, David
AU - Patra, Kailash P.
AU - Flannery, Erika L.
AU - Vinetz, Joseph M.
AU - Renia, Laurent
AU - Sauerwein, Robert W.
AU - Winzeler, Elizabeth A.
AU - Glynne, Richard J.
AU - Diagana, Thierry T.
PY - 2014
Y1 - 2014
N2 - Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
AB - Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
KW - antimalarial agent
KW - artesunate
KW - chloroquine
KW - imidazole derivative
KW - kaf 156
KW - kaf156
KW - mefloquine
KW - piperazine derivative
KW - unclassified drug
KW - KAF156
KW - animal experiment
KW - animal model
KW - Anopheles
KW - antimalarial activity
KW - antimalarial drug susceptibility
KW - article
KW - controlled study
KW - disease elimination
KW - dose time effect relation
KW - drug dose comparison
KW - drug efficacy
KW - drug safety
KW - female
KW - genetic strain
KW - human
KW - human cell
KW - IC 50
KW - in vitro study
KW - in vivo study
KW - malaria control
KW - malaria falciparum
KW - mouse
KW - multiple drug dose
KW - nonhuman
KW - parasite clearance
KW - parasite transmission
KW - Plasmodium falciparum
KW - Plasmodium vivax malaria
KW - priority journal
KW - rodent malaria
KW - schizont
KW - single drug dose
KW - sporozoite
KW - treatment response
KW - animal
KW - drug effects
KW - IC50
KW - Institute for Cancer Research mouse
KW - Malaria, Falciparum
KW - transmission
KW - Animals
KW - Antimalarials
KW - Imidazoles
KW - Inhibitory Concentration 50
KW - Mice
KW - Mice, Inbred ICR
KW - Piperazines
KW - Sporozoites
UR - http://www.scopus.com/inward/record.url?scp=84906079854&partnerID=8YFLogxK
U2 - 10.1128/AAC.02727-13
DO - 10.1128/AAC.02727-13
M3 - Article
VL - 58
SP - 5060
EP - 5067
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 9
ER -