Medicinal Chemistry
Medicinal Chemistry
批准号:
7639081
负责人:
Toni KLINE
金额:
$45.14万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2008
资助国家:
美国
项目状态:
已结题
起止时间:
2008-03-01 至 2009-02-28
关键词:
AcidsAcuteAffinityAgonistAreaBacteriaBiologyBioterrorismBurkholderiaChemicalsChemistryClassCommunicationComplexComputer SimulationDataDevelopmentDrug resistanceEscherichiaEvaluationGoalsGuanosine MonophosphateHumanInfectionLeadLightMediatingMicrobiologyMolecularPathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPropertyProteinsProteomicsPseudomonas InfectionsReportingResearchResistanceSignal TransductionSignaling MoleculeSystemTherapeuticType III Secretion System PathwayValidationVirulenceYersinia pestisanalogantimicrobial drugbasebis(3&apos,5&apos)-cyclic diguanylic aciddesigndimerdrug discoveryhigh throughput screeningimprovedinhibitor/antagonistnovelpathogenphosphoric diester hydrolaseresistance mechanismresponsesmall moleculetherapeutic targettool
中文摘要
细菌的交流,耐药性和毒力机制仍然是小
英文摘要
Bacterial communication, resistance, and virulence mechanisms remain underrepresented targets for small
molecule-based medicinal chemistry. The relatively narrow focus of antimicrobial drug discovery is
particularly acute in the area of Gram-negative infections, a class that includes pathogens relevant to
potential acts of bioterrorism (Yersinia pestis, Burkholderia pseudomalleii), emerging infections (Escherichia
co// O157:H7), and persistent infections (Pseudomonas aeruginsoa). There are compelling reasons to
understand virulence mechanisms, and to use small molecule chemistry to do so. Drugs directed at
virulence targets are less likely to provoke a resistance response in the bacteria. Novel drugs, and drugs
directed at novel targets, are also less likely to be deflected by pre-existing drug resistance mechanisms in
the bacteria. In light of this, we are developing novel compounds directed at novel virulence targets as
potential therapeutics and as microbiology research tools. In this proposal we outline our progress and plans
using chemical biology/medicinal chemistry to understand and ultimately manipulate two virulence-related
systems, type III secretion (T3SS) and bis-(3'-5') cyclic diguanilic acid (c-di-GMP) signaling. For both
projects, the goals are to synthesize molecules that will (a) enable understanding the molecular details of the
dynamics and architechture of these complex oligomeric systems,(b) to validate targets within these
systems for drug discovery, and (c) to produce lead candidates for development as human therapeutics
targeting these systems. In the T3SS project we have synthesized derivatives of our original high-throughput
screen hit (TTSS29) that not only improve upon its activity 10 and 100-fold but also improve the potential of
this chemotype to be a realistic therapeutic. When considered along with the earlier purchased compounds,
our panel of novel synthetic compounds¿now over 50- provide the guidance we need for further
refinements in the 2-iminothiazolidinone class to which TTSS29 belongs. In the c-di-GMP project, we have
synthesized a novel class stable analogs of the known signaling molecule (i.e. c-di-GMP itself) and several
seco-di-GMP analogs of the acyclic dimer, pGpG, a molecule that may have as-yet-unreported signaling
properties of its own. Currently, no small molecule inhibitors, agonists, or antagonists of the c-di-GMP
pathway have been reported. We will evaluate our novel c-di-GMP and s-di-GMP analogs as inhibitors of
the upregulating cyclase, the downregulating phosphodiesterase, and as agonists /antagonists of known cdi-
GMP mediated responses. From these data, and from an in silico screen we describe herein, we will
create new compounds intended to validate, and ultimately exploit, c-di-GMP signalling as a therapeutic
target in Gram-negative infections .
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Antibiotic Drug Discovery
-
批准号:8236979
-
项目类别:
-
资助金额:$48.72万
-
财政年份:2011
-
负责人:Toni KLINE
-
依托单位:
Antibiotic Drug Discovery
-
批准号:7675846
-
项目类别:
-
资助金额:$47.93万
-
财政年份:2009
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负责人:Toni KLINE
-
依托单位:
Tumor-selective Anticancer Prodrugs
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批准号:6552125
-
项目类别:
-
资助金额:$12.88万
-
财政年份:2002
-
负责人:Toni KLINE
-
依托单位:
SYNTHETIC ANTAGONISTS OF THE PSEUDOMONAS AUTOINDUCER
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批准号:2712395
-
项目类别:
-
资助金额:$10.0万
-
财政年份:1998
-
负责人:Toni KLINE
-
依托单位:
Antibiotic Drug Discovery
-
批准号:8377658
-
项目类别:
-
资助金额:$65.9万
-
财政年份:--
-
负责人:Toni KLINE
-
依托单位:
Antibiotic Drug Discovery
-
批准号:8051659
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项目类别:
-
资助金额:$49.45万
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财政年份:--
-
负责人:Toni KLINE
-
依托单位:
Antibiotic Drug Discovery
-
批准号:8447083
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项目类别:
-
资助金额:$57.89万
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财政年份:--
-
负责人:Toni KLINE
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依托单位:
海外基金