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Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

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Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
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Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These...
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Inhibitors of Viral Protein Synthesis01:30

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Protein synthesis is indispensable for viral replication, as viruses lack the cellular machinery required for this process and must hijack the host's translational apparatus. In response, host cells deploy a critical innate immune defense involving interferons, specialized cytokines that play a central role in inhibiting viral propagation.Upon viral detection, infected cells release interferons that bind to receptors on adjacent uninfected cells, activating the JAK-STAT signaling pathway and...
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Related Experiment Video

Updated: May 5, 2026

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Structural Basis for HIV-1 Maturation Inhibition by PF-46396 Determined by MAS NMR.

Roman Zadorozhnyi1,2, Caitlin M Quinn1, Kaneil K Zadrozny3

  • 1Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.

Journal of the American Chemical Society
|September 9, 2025
PubMed
Summary
This summary is machine-generated.

This study reveals how the HIV-1 maturation inhibitor PF-46396 binds to viral proteins, offering insights into antiretroviral therapy and potential drug resistance mechanisms. Understanding this interaction is key for developing new HIV treatments.

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Area of Science:

  • Structural Biology
  • Virology
  • Medicinal Chemistry

Background:

  • HIV-1 maturation inhibitors targeting the capsid protein (CA) C-terminal domain (CACTD)-spacer peptide 1 (SP1) junction are promising antiretroviral therapies.
  • Stabilizing this junction in the immature Gag lattice is a key mechanism of action.

Purpose of the Study:

  • To determine the atomic-resolution structure of CACTD-SP1 assemblies bound to PF-46396 and inositol hexakisphosphate (IP6).
  • To elucidate the binding modes of PF-46396 enantiomers and their effect on IP6 dynamics and orientation.

Main Methods:

  • Magic Angle Spinning (MAS) Nuclear Magnetic Resonance (NMR) spectroscopy was employed to determine the structure.
  • Analysis of distinct binding modes of PF-46396 enantiomers.

Main Results:

  • Atomic-resolution structures revealed distinct binding modes for PF-46396 enantiomers, yet similar anti-HIV potency.
  • PF-46396 binding arrested IP6 dynamics in the six-helix bundle pore, with unique IP6 orientations induced by each enantiomer.
  • Evidence suggests the presence of a monoanionic IP6 form within the complex.

Conclusions:

  • The study establishes the structural basis for PF-46396's mechanism of action as an HIV-1 maturation inhibitor.
  • The findings provide a mechanistic model for understanding and potentially overcoming drug resistance to this class of antivirals.