Inhibition of hepadnavirus reverse transcriptase-epsilon RNA interaction by porphyrin compounds.
The hepatitis B virus (HBV) reverse transcriptase (RT) plays a multitude of fundamental roles in the viral life cycle and is the key target in the development of anti-HBV chemotherapy. We report here that the endogenous small molecule iron protoporphyrin IX (hemin) and several related porphyrin compounds potently blocked a critical RT interaction with the viral RNA packaging signal/origin of replication, called epsilon. As RT-epsilon interaction is essential for the initiation of viral reverse transcription, which is primed by RT itself (protein priming), the porphyrin compounds dramatically suppressed the protein-priming reaction. Further studies demonstrated that these compounds could target the unique N-terminal domain of the RT protein, the so-called terminal protein. Hemin and related porphyrin compounds thus represent a novel class of agents that can block HBV RT functions through a mechanism and target that are completely distinct from those of existing anti-HBV drugs.
Lin
Li
L
Department of Microbiology and Immunology-H107, Penn State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA.
Hu
Jianming
J
D001665:Binding Sites; D006427:Hemin / Q000494:pharmacology; D006515:Hepatitis B virus / Q000201:enzymology*; D015394:Molecular Structure; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000378:metabolism*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012261:Ribonucleoproteins / Q000378:metabolism
D011166:Porphyrins; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D012261:Ribonucleoproteins; D006427:Hemin; D012194:RNA-Directed DNA Polymerase