The Integration of High Throughput Technologies for Drug Discovery

Sabbatini, Gregory P.; Shirley, William A.; Coffen, David L.

doi:10.1089/10870570152488400

Cited by 3 publications

(2 citation statements)

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“…Focussed libraries are often the second step in the discovery process following the identification of a lead molecule. Increasingly, concerns regarding the ultimate 'drug likeness' of a molecule have permeated the earliest steps in library construction and library synthesis is often preceded by a filtering out of molecules with characteristics incompatible with oral absorption or rapid metabolism [66,67].…”

Section: Combinatorial Approaches To Lead Optimizationmentioning

confidence: 99%

Modern Drug Development

Barry¹

2002

Issues in Infectious Diseases

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Current recommended drug therapy for tuberculosis (TB) consists of 2 months of daily treatment with isoniazid, rifampicin, and pyrazinamide, often with the inclusion of ethambutol in areas where drug resistance is common. This 2-month course of therapy is usually sufficient to render all patients sputum culture negative but an additional 4 months of therapy is required to guarantee that patients will not relapse with disease following completion of their regimen [1]. This optimum 'short-course' chemotherapy was determined to be effective through an extraordinary series of field trials conducted in TB patients globally from 1946 to 1976 and it is highly effective -if the entire 6-month course is completed, 95% or more of patients can be cured of their disease [2].The reality of the situation is that TB control programs now focus their resources on increasingly complex logistical solutions to the problem of ensuring that patients complete this extensive chemotherapy rather than on drugs per se or ancillary activities such as surveillance and detection of new cases. Direct supervision of therapy by a health care provider (originally implemented by the British Medical Research Council in 1958 in Hong Kong and Madras but then later re-marketed as ' DOT' or Directly Observed Therapy [3]) is now considered standard despite that this requires the vast majority of the resources for TB 'chemotherapy' go not to pay for the drugs, but for the support infrastructure necessary to deliver them effectively [4]. Despite heroic efforts by the international community, in many regions of the world TB control programs either do not exist or are loosely organized coalitions with little understanding of the principles of TB therapy and with little access to high-quality drugs or a stable system through which to supervise their administration for such an extensive time period.A major contributing factor, therefore, to the difficulty of achieving worldwide success with TB eradication stems from the fundamental limitation

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Section: Combinatorial Approaches To Lead Optimizationmentioning

confidence: 99%

Modern Drug Development

Barry¹

2002

Issues in Infectious Diseases

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“…One strategy, high-throughput screening and its corresponding microarrays, chemical libraries, and robotics systems, sought to increase quantity of leads produced by increasing the sheer number of lead discovery experiments run (3)(4)(5)(6). The other strategy, rational drug design, sought to increase the quality of the lead (7-9) -technologies like gene therapy, though their clinical potential has tarnished in recent years, promised to produce substances specifically designed around existing knowledge on a disease.…”

Section: Overviewmentioning

confidence: 99%

Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study

Jennifer¹

2002

Front Biosci

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As new lead discovery technologies of high throughput screening and rational drug design have been incorporated into pharmaceutical and biotechnology drug discovery programs, researchers have focused on the applying these new technologies in diseases traditionally neglected by for-profit drug discovery efforts. This article reviews general trends in orphan disease lead discovery, identifies best practices of orphan market drug discovery and provides an overview of recent ALS lead discovery programs and drug development according to these metrics. Best practices in orphan market drug discovery embodied by programs like the NIH Anticonvulsant Screening Program include the (1) management of timelines and priorities, (2) engagement of for-profit partners, (3) creative application of technology, (4) collaboration, and (5) flexibility. Recent trends in ALS lead discovery have been shaped not only by the predominance of animal models of disease over in vitro models, but also by the successes and best practices of these earlier orphan market drug discovery programs. The ALS Treatment Initiative, the Johns Hopkins Center for ALS Research, the ALS Association, and the ALS Therapy Development Foundation have all initiated lead discovery programs in the past several years which seek to utilize existing experimental models of the disease and challenge assumptions about the linear nature of the lead discovery and development process. The compounds currently in clinical evaluation for ALS were identified as leads from a variety of sources, further reinforcing the transforming effect these new lead discovery programs have had on drug discovery and development in ALS. We conclude our review with an overview of the challenges and opportunities lead discovery in ALS currently faces, ultimately concluding that ALS lead discovery, and indeed orphan market drug discovery in general, would most benefit from more centralized lead discovery management, expanded national access to core facilities for lead discovery, and matrixed simultaneous screening of multiple compounds for multiple neglected diseases.

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Development of a Cell-Based Enzyme-Linked Immunosorbent Assay for High-Throughput Screening of HIV Type 1 Entry Inhibitors Targeting the Coreceptor CXCR4

Zhao

Liang

Schols

et al. 2003

AIDS Research and Human Retroviruses

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CXCR4, a coreceptor for human immunodeficiency virus type 1 (HIV-1) X4 virus, plays an important role in virus entry into the target cells. Antiviral agents that bind to CXCR4 are expected to inhibit HIV-1 entry. A cell-based enzyme-linked immunosorbent assay (ELISA) was developed utilizing an anti-CXCR4 monoclonal antibody, 12G5, and cells expressing CD4 and CXCR4, U373-MAGI-CXCR4(CEM) cells. Using this assay, we demonstrated that 12G5 specifically binds to the CXCR4-expressing cells, but not to CCR5-expressing cells and cells without CXCR4 and CCR5, consistent with the results obtained by using flow cytometry. The well-characterized CXCR4 antagonists, T22, T14012 (a downsized analog of T-22), and AMD3100, effectively inhibited 12G5 binding to CXCR4-expressing cells, while HIV-1 entry inhibitors targeting CD4 and gp41 as well as HIV-1 reverse transcriptase and protease inhibitors did not block the binding of 12G5 to U373-MAGI-CXCR4(CEM) cells. The prepared plates containing the fixed cells could be stored at -80 degrees C for at least 5 months without affecting the cell reactivity with 12G5, which enhances the convenience of this method. This suggests that the cell-based ELISA is specific, sensitive, convenient, rapid, and economic. With a robotic sample processing system, this assay can be used for high-throughput screening of HIV-1 entry inhibitors targeted to the HIV-1 coreceptor CXCR4.

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The Integration of High Throughput Technologies for Drug Discovery

Cited by 3 publications

References 0 publications

Modern Drug Development

Modern Drug Development

Novel trends in orphan market drug discovery: amyotrophic lateral sclerosis as a case study

Development of a Cell-Based Enzyme-Linked Immunosorbent Assay for High-Throughput Screening of HIV Type 1 Entry Inhibitors Targeting the Coreceptor CXCR4

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