Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase

Jieying Liu; David B. Bolstad; Adrienne E. Smith; Nigel D. Priestley; Dennis L. Wright; Amy C. Anderson

doi:10.1016/j.chembiol.2008.07.013

Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase

Jieying Liu
, David B. Bolstad
, Adrienne E. Smith
, Nigel D. Priestley
, Dennis L. Wright
, Amy C. Anderson

Chemistry and Biochemistry

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

38 Scopus citations

Abstract

Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 Å resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

Original language	English
Pages (from-to)	990-996
Number of pages	7
Journal	Chemistry and Biology
Volume	15
Issue number	9
DOIs	https://doi.org/10.1016/j.chembiol.2008.07.013
State	Published - Sep 22 2008

Funding

The authors thank Kathleen Frey for preparing and testing compounds against hDHFR, Phil Pelphrey and Jennifer Beierlein for synthesizing compound 11 , Erin Bolstad for preparing Figure 3 A, Brookhaven National Laboratory for providing access to beamline X25A, and the NIH for funding (GM067542). N.D.P. is a founder of Promiliad Biopharma, Inc.

Funder number
R01GM067542

Keywords

CHEMBIO

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10.1016/j.chembiol.2008.07.013

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title = "Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase",

abstract = "Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 {\AA} resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.",

keywords = "CHEMBIO",

author = "Jieying Liu and Bolstad, \{David B.\} and Smith, \{Adrienne E.\} and Priestley, \{Nigel D.\} and Wright, \{Dennis L.\} and Anderson, \{Amy C.\}",

note = "Funding Information: The authors thank Kathleen Frey for preparing and testing compounds against hDHFR, Phil Pelphrey and Jennifer Beierlein for synthesizing compound 11 , Erin Bolstad for preparing Figure 3 A, Brookhaven National Laboratory for providing access to beamline X25A, and the NIH for funding (GM067542). N.D.P. is a founder of Promiliad Biopharma, Inc. ",

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T1 - Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase

AU - Liu, Jieying

AU - Bolstad, David B.

AU - Smith, Adrienne E.

AU - Priestley, Nigel D.

AU - Wright, Dennis L.

AU - Anderson, Amy C.

N1 - Funding Information: The authors thank Kathleen Frey for preparing and testing compounds against hDHFR, Phil Pelphrey and Jennifer Beierlein for synthesizing compound 11 , Erin Bolstad for preparing Figure 3 A, Brookhaven National Laboratory for providing access to beamline X25A, and the NIH for funding (GM067542). N.D.P. is a founder of Promiliad Biopharma, Inc.

PY - 2008/9/22

Y1 - 2008/9/22

N2 - Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 Å resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

AB - Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 Å resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.

KW - CHEMBIO

UR - https://www.scopus.com/pages/publications/51649118086

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SN - 1074-5521

VL - 15

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EP - 996

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 9

ER -

Structure-Guided Development of Efficacious Antifungal Agents Targeting Candida glabrata Dihydrofolate Reductase

Abstract

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Keywords

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