Antiviral drug recognition and elevator-type transport motions of CNT3.

Publication date: Feb 28, 2024

Nucleoside analogs have broad clinical utility as antiviral drugs. Key to their systemic distribution and cellular entry are human nucleoside transporters. Here, we establish that the human concentrative nucleoside transporter 3 (CNT3) interacts with antiviral drugs used in the treatment of coronavirus infections. We report high-resolution single-particle cryo-electron microscopy structures of bovine CNT3 complexed with antiviral nucleosides N-hydroxycytidine, PSI-6206, GS-441524 and ribavirin, all in inward-facing states. Notably, we found that the orally bioavailable antiviral molnupiravir arrests CNT3 in four distinct conformations, allowing us to capture cryo-electron microscopy structures of drug-loaded outward-facing and drug-loaded intermediate states. Our studies uncover the conformational trajectory of CNT3 during membrane transport of a nucleoside analog antiviral drug, yield new insights into the role of interactions between the transport and the scaffold domains in elevator-like domain movements during drug translocation, and provide insights into the design of nucleoside analog antiviral prodrugs with improved oral bioavailability.

Concepts Keywords
Antiviral Analog
Bioavailability Antiviral
Cnt3 Cnt3
Coronavirus Cryo
Elevator Drug
Drugs
Electron
Elevator
Facing
Insights
Loaded
Microscopy
Nucleoside
States
Transport

Semantics

Type Source Name
disease MESH coronavirus infections
disease VO report
drug DRUGBANK Ribavirin

Original Article

(Visited 1 times, 1 visits today)