Natural Product Scaffolds as Leads to Drugs

Newman, David J.; Cragg, Gordon M.

doi:10.4155/fmc.09.113

Cited by 93 publications

(54 citation statements)

References 91 publications

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“…Natural products are a unique source of structural complexity and stereodiversity, and they have been exploited by many in the pursuit of new medicine (24). However, the large-scale screening for natural products able to kill bacteria in vitro, which was the basis for the boom of antibiotics in the 1950s, was not successful for antivirals (10).…”

Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

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Section: Discussionmentioning

confidence: 99%

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Bonavia¹,

Franti²,

Keaney³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…biosynthetic gene clusters | natural products | Burkholderia thailandensis | regulation | virulence B acterial secondary metabolites represent a dominant source of pharmaceutical compounds and comprise some of our most celebrated cures (1,2). The genes responsible for biosynthesizing these complex molecules, such as vancomycin or bleomycin, are often clustered in bacterial chromosomes (3).…”

mentioning

confidence: 99%

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Mao

Bushin

Moon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

140

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Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacterium Burkholderia thailandensis E264 using genetic, transcriptomic, metabolomic, and chemical approaches. We report that a previously unknown, quorum-sensing-controlled LysR-type transcriptional regulator, which we name ScmR (for secondary metabolite regulator), serves as a global gatekeeper of secondary metabolism and a repressor of numerous BGCs. Transcriptionally, we find that 13 of the 20 BGCs in B. thailandensis are significantly (threefold or more) upor down-regulated in a scmR deletion mutant (ΔscmR). Metabolically, the ΔscmR strain displays a hyperactive phenotype relative to wild type and overproduces a number of compound families by 18-to 210-fold, including the silent virulence factor malleilactone. Accordingly, the ΔscmR mutant is hypervirulent both in vitro and in a Caenorhabditis elegans model in vivo. Aside from secondary metabolism, ScmR also represses biofilm formation and transcriptionally activates ATP synthesis and stress response. Collectively, our data suggest that ScmR is a pleiotropic regulator of secondary metabolism, virulence, biofilm formation, and other stationary phase processes. A model for how the interplay of ScmR with pathwayspecific transcriptional regulators coordinately silences virulence factor production is proposed.biosynthetic gene clusters | natural products | Burkholderia thailandensis | regulation | virulence

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“…The quality of a compound collection greatly influences the hit rates of any screening endeavor and therefore "quality" of molecules has become the key criterion in design and synthesis of compound collections [3,4]. One source of inspiration for this quality is the structural diversity and complexity of natural products, which remain the major source of bioactive hit and lead structures in drug discovery till date [5][6][7]. Traditionally, natural products and their analogs are synthesized in what is famously termed as total synthesis or target oriented synthesis (TOS), wherein simple building blocks are assembled stepwise in a long and often tedious synthesis route to generate a complex natural product [8][9][10].…”

Section: The Biological/pharmacological Problem: Discovering Small Bimentioning

confidence: 99%

Scaffold Diversity Synthesis with Branching Cascades Strategy

Kumar

2014

Concepts and Case Studies in Chemical Biology

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Natural Product Scaffolds as Leads to Drugs

Cited by 93 publications

References 91 publications

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV)

Discovery of scmR as a global regulator of secondary metabolism and virulence in Burkholderia thailandensis E264

Scaffold Diversity Synthesis with Branching Cascades Strategy

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