Current Progress on Equilibrative Nucleoside Transporter Function and Inhibitor Design

S Rehan, S Shahid, Tiina Salminen, Jaakola V-P, VO Paavilainen

Forskningsoutput: TidskriftsbidragÖversiktsartikelPeer review

4 Citeringar (Scopus)

Sammanfattning

Physiological nucleosides are used for the synthesis of DNA, RNA, and ATP in the cell and serve as universal mammalian signaling molecules that regulate physiological processes such as vasodilation and platelet aggregation by engaging with cell surface receptors. The same pathways that allow uptake of physiological nucleosides mediate the cellular import of synthetic nucleoside analogs used against cancer, HIV, and other viral diseases. Physiological nucleosides and nucleoside drugs are imported by two families of nucleoside transporters: the SLC28 concentrative nucleoside transporters (CNTs) and SLC29 equilibrative nucleoside transporters (ENTs). The four human ENT paralogs are expressed in distinct tissues, localize to different subcellular sites, and transport a variety of different molecules. Here we provide an overview of the known structure-function relationships of the ENT family with a focus on ligand binding and transport in the context of a new hENT1 homology model. We provide a generic residue numbering system for the different ENTs to facilitate the interpretation of mutational data produced using different ENT homologs. The discovery of paralog-selective small-molecule modulators is highly relevant for the design of new therapies and for uncovering the functions of poorly characterized ENT family members. Here, we discuss recent developments in the discovery of new paralog-selective small-molecule ENT inhibitors, including new natural product-inspired compounds. Recent progress in the ability to heterologously produce functional ENTs will allow us to gain insight into the structure and functions of different ENT family members as well as the rational discovery of highly selective inhibitors.
OriginalspråkOdefinierat/okänt
Sidor (från-till)953–968
Antal sidor16
TidskriftSlas Discovery
Volym24
Utgåva10
DOI
StatusPublicerad - 2019
MoE-publikationstypA2 Granska artikel i en vetenskaplig tidskrift

Nyckelord

  • membrane transporter
  • equilibrative nucleoside transporter (ENT)
  • structural biology
  • NUCLEOSIDE

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