Molecular wedge could lead normal virus formation astray

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   Source:  Virus Weekly, June 18, 2002 p3.
                                                                              
    Title:  Molecular wedge could lead normal virus formation astray in
            hepatitis B.(Brief Article)
                                                                              
Subjects:  Hepatitis B - Development and progression
Locations:  United States
SIC code:  8730
                                                                              
Electronic Collection:  A87152119
                   RN:  A87152119
                                                                              

Full Text COPYRIGHT 2002 NewsRX

2002 JUN 18 - (NewsRx.com & NewsRx.net) -- by Sonia Nichols, senior medical writer - Small molecules that act like secret agents could be key to
disrupting the formation of hepatitis B and other viruses, suggest researchers at the University of Oklahoma.

The scientists think a molecule known as bis-ANS and others like it could form the underpinnings for new types of antiviral agents in the future.

Explaining that HBV capsids can be produced in the lab, Adam Zlotnick and
colleagues at the University of Oklahoma Health Sciences Center recently
described in the Journal of Virology how bis-ANS acts as a wedge to disrupt
capsid assembly. After binding to capsid building blocks, the molecule, which
inactivates mechanisms resembling enzymes, works slyly to form nonsense-type polymers instead of a capsid.

"Using equilibrium dialysis to investigate binding of bis-ANS to free capsid
protein, we found that only one bis-ANS molecule binds per capsid protein
dimer, with an association energy of -28 [plus-or-minus sign] 2.0 kJ/mol,"
Zlotnick and coauthors noted.

Chromatographic analysis indicated that bis-ANS used ionic strength to disrupt particle assembly, and its binding energy was almost equivalent to that reportedly demonstrated in unassembled protein, according to Zlotnick and colleagues (A small molecule inhibits and misdirects assembly of hepatitis B virus capsids, J Virol, 2002;76(10):4848-4854).

"The data indicate that capsid protein bound to bis-ANS did not participate in assembly; this mechanism of assembly inhibition is analogous to competitive or noncompetitive inhibition of enzymes," the investigators pointed out.

Instead of allowing normal capsid formation, bis-ANS caused aberrant,
noncapsid polymers to form during the dialysis experiments.

"We propose that bis-ANS acts as a molecular "wedge" that interferes with
normal capsid protein geometry and capsid formation; such wedges may represent a new class of antiviral agent," Zlotnick and colleagues proposed.

The corresponding author for this study is Adam Zlotnick, P.O.B. 26901, BRC
464, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA. E-mail: [email protected].

Key points reported in this study include:

* A small molecule known as bis-ANS binds to capsid protein in HBV and is able to disrupt normal capsid assembly

* Bis-ANS causes the formation of aberrant, noncapsid polymers

* Molecules like bis-ANS act like a wedge to disrupt normal capsid
construction, and could potentially be used in the clinical setting as
antivirals

This article was prepared by Virus Weekly editors from staff and other
reports.
                                                                              
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