Strategies for Antiviral Drug Discovery

Jones, PS

doi:10.1177/095632029800900401

Cited by 34 publications

(12 citation statements)

References 106 publications

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“…Specific and sensitive molecular screens are readily derived using the same molecular biology technologies that are driving the genome programs and using the sequence data from those studies to give high-throughput robotic screening. Initial success in the rational design for targets such as HIV-1 protease (243,461,482,496,497) leads to strategies for rational design involving gene identification (78,280), metabolic pathway analysis (252), or determination of protein-protein interactions using affinity methods such as the yeast two-hybrid system, phage display (363), or fluorescent-protein biosensors (167), structure prediction (CASP http://PredictionCenter.llnl.gov/) (161,242,305,503,507), and modelling (63).…”

Section: Genomicsmentioning

confidence: 99%

Search and Discovery Strategies for Biotechnology: the Paradigm Shift

Bull

Ward

Goodfellow

2000

Microbiol Mol Biol Rev

418

250

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SUMMARY Profound changes are occurring in the strategies that biotechnology-based industries are deploying in the search for exploitable biology and to discover new products and develop new or improved processes. The advances that have been made in the past decade in areas such as combinatorial chemistry, combinatorial biosynthesis, metabolic pathway engineering, gene shuffling, and directed evolution of proteins have caused some companies to consider withdrawing from natural product screening. In this review we examine the paradigm shift from traditional biology to bioinformatics that is revolutionizing exploitable biology. We conclude that the reinvigorated means of detecting novel organisms, novel chemical structures, and novel biocatalytic activities will ensure that natural products will continue to be a primary resource for biotechnology. The paradigm shift has been driven by a convergence of complementary technologies, exemplified by DNA sequencing and amplification, genome sequencing and annotation, proteome analysis, and phenotypic inventorying, resulting in the establishment of huge databases that can be mined in order to generate useful knowledge such as the identity and characterization of organisms and the identity of biotechnology targets. Concurrently there have been major advances in understanding the extent of microbial diversity, how uncultured organisms might be grown, and how expression of the metabolic potential of microorganisms can be maximized. The integration of information from complementary databases presents a significant challenge. Such integration should facilitate answers to complex questions involving sequence, biochemical, physiological, taxonomic, and ecological information of the sort posed in exploitable biology. The paradigm shift which we discuss is not absolute in the sense that it will replace established microbiology; rather, it reinforces our view that innovative microbiology is essential for releasing the potential of microbial diversity for biotechnology penetration throughout industry. Various of these issues are considered with reference to deep-sea microbiology and biotechnology.

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Section: Genomicsmentioning

confidence: 99%

Search and Discovery Strategies for Biotechnology: the Paradigm Shift

Bull

Ward

Goodfellow

2000

Microbiol Mol Biol Rev

418

250

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“…Promising drug candidates from high-throughput screens can be further refined chemically through structural modifications based upon molecular modeling principles in an effort to increase antiviral activity while decreasing toxicity. Such procedures led to the development of the current class of protease inhibitors (19). However, most initial screening focuses upon a single, well-defined aspect of replication with cell-free systems.…”

mentioning

confidence: 99%

Toward the Development of a Virus-Cell-Based Assay for the Discovery of Novel Compounds against Human Immunodeficiency Virus Type 1

Adelson

Pacchia

Kaul

et al. 2003

Antimicrob Agents Chemother

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The emergence of human immunodeficiency virus type 1 (HIV-1) strains resistant to highly active antiretroviral therapy necessitates continued drug discovery for the treatment of HIV-1 infection. Most current drug discovery strategies focus upon a single aspect of HIV-1 replication. A virus-cell-based assay, which can be adapted to high-throughput screening, would allow the screening of multiple targets simultaneously. HIV-1-based vector systems mimic the HIV-1 life cycle without yielding replication-competent virus, making them potentially important tools for the development of safe, wide-ranging, rapid, and cost-effective assays amenable to high-throughput screening. Since replication of vector virus is typically restricted to a single cycle, a crucial question is whether such an assay provides the needed sensitivity to detect potential HIV-1 inhibitors. With a stable, inducible vector virus-producing cell line, the inhibitory effects of four reverse transcriptase inhibitors (zidovudine, stavudine, lamivudine, and didanosine) and one protease inhibitor (indinavir) were assessed. It was found that HIV-1 vector virus titer was inhibited in a single cycle of replication up to 300-fold without affecting cell viability, indicating that the assay provides the necessary sensitivity for identifying antiviral molecules. Thus, it seems likely that HIV-1-derived vector systems can be utilized in a novel fashion to facilitate the development of a safe, efficient method for screening compound libraries for anti-HIV-1 activity.Currently, the principal regimen for the treatment of individuals infected with human immunodeficiency virus type 1 (HIV-1) involves highly active antiretroviral therapy, which typically includes a combination of a protease inhibitor and a nucleoside and/or nonnucleoside reverse transcriptase (RT) inhibitor. HIV-1 protease inhibitors such as indinavir, ritonavir, and saquinavir prevent proteolytic processing of immature viral polyproteins to produce mature infectious virions (37) Nucleoside RT inhibitors such as zidovudine, didanosine, lamivudine, and stavudine lack the 3Ј-OH moiety on the ribose sugar and act as chain terminators when incorporated into the elongating DNA chain by the HIV-1 RT, while the nonnucleoside RT inhibitors such as efavirenz, delavirdine, and nevirapine represent a class of diverse polycyclic compounds that bind to a site near the catalytic domain of RT and interfere with polymerase activity (26).Highly active antiretroviral therapy has greatly decreased morbidity and mortality for millions of HIV-1-infected individuals over the past several years. However, 10 to 50% of pa-

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“…The potential of helicases as antiviral drug targets has recently been reviewed [32][33][34][35][36] . Unlike retroviruses, two other human viruses, HSV and human papillomavirus (HPV), physically encode their own helicases.…”

Section: Viral Helicases As Antiviral Drug Targetsmentioning

confidence: 99%

Viral and cellular RNA helicases as antiviral targets

Kwong

Rao

Jeang

2005

Nat Rev Drug Discov

200

188

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Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.

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Strategies for Antiviral Drug Discovery

Cited by 34 publications

References 106 publications

Search and Discovery Strategies for Biotechnology: the Paradigm Shift

Search and Discovery Strategies for Biotechnology: the Paradigm Shift

Toward the Development of a Virus-Cell-Based Assay for the Discovery of Novel Compounds against Human Immunodeficiency Virus Type 1

Viral and cellular RNA helicases as antiviral targets

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