A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly.
Heteroaryldihydropyrimidines (HAPs) are a new class of antivirals inhibiting production of hepatitis B virus (HBV) virions in tissue culture. Here, we examine the effect of a representative HAP molecule, methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1), on the in vitro assembly of HBV capsid protein (Cp). HAP-1 enhances the rate and extent of Cp assembly over a broad concentration range. Aberrant particles, dominated by hexagonal arrays of Cp, were observed from assembly reactions with high HAP-1 concentrations. HAP-1 also led to dissociation of metastable HBV capsids, overcoming a kinetic barrier to dissociation by scavenging Cp and redirecting its assembly into hexamer-rich structures. Thus, HAP drugs act as allosteric effectors that induce an assembly-active state and, at high concentration, preferentially stabilize noncapsid polymers of Cp. HAP compounds may have multiple effects in vivo stemming from inappropriate assembly of Cp. These results show that activating and deregulating virus assembly may be a powerful general approach for antiviral therapeutics.
Stray
Stephen J
SJ
Department of Biochemistry and Molecular Biology BRC 464, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190, USA.
Bourne
Christina R
CR
Punna
Sreenivas
S
Lewis
Warren G
WG
Finn
M G
MG
Zlotnick
Adam
A
D000494:Allosteric Regulation / Q000187:drug effects; D002213:Capsid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D019281:Dimerization; D006515:Hepatitis B virus / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development* / Q000648:ultrastructure; D007700:Kinetics; D008958:Models, Molecular; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019065:Virus Assembly / Q000187:drug effects*
D011725:Pyridines; D011743:Pyrimidines; C502271:methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate