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- Galetin, Aleksandra, et al.
(författare)
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Membrane transporters in drug development and as determinants of precision medicine
- 2024
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Ingår i: NATURE REVIEWS DRUG DISCOVERY. - 1474-1776 .- 1474-1784.
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Forskningsöversikt (refereegranskat)abstract
- The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions. Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
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| 2. |
- Munke, Anna, et al.
(författare)
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Primordial Capsid and Spooled ssDNA Genome Structures Unravel Ancestral Events of Eukaryotic Viruses
- 2022
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Marine algae viruses are important for controlling microorganism communities in the marine ecosystem and played fundamental roles during the early events of viral evolution. Here, we have focused on one major group of marine algae viruses, the single-stranded DNA (ssDNA) viruses from the Bacilladnaviridae family. We present the capsid structure of the bacilladnavirus Chaetoceros tenuissimus DNA virus type II (CtenDNAV-II), determined at 2.4-Å resolution. A structure-based phylogenetic analysis supported the previous theory that bacilladnaviruses have acquired their capsid protein via horizontal gene transfer from a ssRNA virus. The capsid protein contains the widespread virus jelly-roll fold but has additional unique features; a third β-sheet and a long C-terminal tail. Furthermore, a low-resolution reconstruction of the CtenDNAV-II genome revealed a partially spooled structure, an arrangement previously only described for dsRNA and dsDNA viruses. Together, these results exemplify the importance of genetic recombination for the emergence and evolution of ssDNA viruses and provide important insights into the underlying mechanisms that dictate genome organization.IMPORTANCE Single-stranded DNA (ssDNA) viruses are an extremely widespread group of viruses that infect diverse hosts from all three domains of life, consequently having great economic, medical, and ecological importance. In particular, bacilladnaviruses are highly abundant in marine sediments and greatly influence the dynamic appearance and disappearance of certain algae species. Despite the importance of ssDNA viruses and the last couple of years' advancements in cryo-electron microscopy, structural information on the genomes of ssDNA viruses remains limited. This paper describes two important achievements: (i) the first atomic structure of a bacilladnavirus capsid, which revealed that the capsid protein gene presumably was acquired from a ssRNA virus in early evolutionary events; and (ii) the structural organization of a ssDNA genome, which retains a spooled arrangement that previously only been observed for double-stranded viruses.
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