Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

Laxman Nallan; Kevin D. Bauer; Pravin Bendale; Kasey Rivas; Kohei Yokoyama; Carolyn P. Hornéy; Prakash Rao Pendyala; David Floyd; Louis J. Lombardo; David K. Williams; Andrew Hamilton; Said Sebti; William T. Windsor; Patricia C. Weber; Frederick S. Buckner; Debopam Chakrabarti; Michael H. Gelb; Wesley C. Van Voorhis

doi:10.1021/jm0491039

Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

Laxman Nallan, Kevin D. Bauer, Pravin Bendale, Kasey Rivas, Kohei Yokoyama, Carolyn P. Hornéy, Prakash Rao Pendyala, David Floyd, Louis J. Lombardo, David K. Williams, Andrew Hamilton, Said Sebti, William T. Windsor, Patricia C. Weber, Frederick S. Buckner, Debopam Chakrabarti, Michael H. Gelb, Wesley C. Van Voorhis

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparurn (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THO PFTIs with antimalaria activity.

Original language	English (US)
Pages (from-to)	3704-3713
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	48
Issue number	11
DOIs	https://doi.org/10.1021/jm0491039
State	Published - Jun 2 2005

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm0491039

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Nallan, L., Bauer, K. D., Bendale, P., Rivas, K., Yokoyama, K., Hornéy, C. P., Pendyala, P. R., Floyd, D., Lombardo, L. J., Williams, D. K., Hamilton, A., Sebti, S., Windsor, W. T., Weber, P. C., Buckner, F. S., Chakrabarti, D., Gelb, M. H., & Van Voorhis, W. C. (2005). Protein farnesyltransferase inhibitors exhibit potent antimalarial activity. Journal of Medicinal Chemistry, 48(11), 3704-3713. https://doi.org/10.1021/jm0491039

Nallan, L, Bauer, KD, Bendale, P, Rivas, K, Yokoyama, K, Hornéy, CP, Pendyala, PR, Floyd, D, Lombardo, LJ, Williams, DK, Hamilton, A, Sebti, S, Windsor, WT, Weber, PC, Buckner, FS, Chakrabarti, D, Gelb, MH & Van Voorhis, WC 2005, 'Protein farnesyltransferase inhibitors exhibit potent antimalarial activity', Journal of Medicinal Chemistry, vol. 48, no. 11, pp. 3704-3713. https://doi.org/10.1021/jm0491039

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title = "Protein farnesyltransferase inhibitors exhibit potent antimalarial activity",

abstract = "New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparurn (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing {"}piggy-backing{"} on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THO PFTIs with antimalaria activity.",

author = "Laxman Nallan and Bauer, {Kevin D.} and Pravin Bendale and Kasey Rivas and Kohei Yokoyama and Horn{\'e}y, {Carolyn P.} and Pendyala, {Prakash Rao} and David Floyd and Lombardo, {Louis J.} and Williams, {David K.} and Andrew Hamilton and Said Sebti and Windsor, {William T.} and Weber, {Patricia C.} and Buckner, {Frederick S.} and Debopam Chakrabarti and Gelb, {Michael H.} and {Van Voorhis}, {Wesley C.}",

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AU - Nallan, Laxman

AU - Bauer, Kevin D.

AU - Bendale, Pravin

AU - Rivas, Kasey

AU - Yokoyama, Kohei

AU - Hornéy, Carolyn P.

AU - Pendyala, Prakash Rao

AU - Floyd, David

AU - Lombardo, Louis J.

AU - Williams, David K.

AU - Hamilton, Andrew

AU - Sebti, Said

AU - Windsor, William T.

AU - Weber, Patricia C.

AU - Buckner, Frederick S.

AU - Chakrabarti, Debopam

AU - Gelb, Michael H.

AU - Van Voorhis, Wesley C.

PY - 2005/6/2

Y1 - 2005/6/2

N2 - New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparurn (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THO PFTIs with antimalaria activity.

AB - New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparurn (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THO PFTIs with antimalaria activity.

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Protein farnesyltransferase inhibitors exhibit potent antimalarial activity

Abstract

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