Virucidal mechanism of action of NVC-422, a novel antimicrobial drug for the treatment of adenoviral conjunctivitis.
Human adenoviral conjunctivitis is a highly contagious eye infection affecting millions of people world-wide. If untreated, it can further develop into keratitis, corneal ulceration, scarring and possible blindness. Despite the significant patient morbidity and socio-economic costs, it is an unmet medical need with no FDA approved treatment. Here, we demonstrate the virucidal activity of NVC-422 (N,N-dichloro-2,2-dimethyltaurine) against adenovirus type 5 (Ad5) and investigated its mechanism of action of Ad5 inactivation. NVC-422 inhibits Ad5-induced loss of cell viability in vitro with 50% inhibitory concentration (IC(50)) ranging from 9 to 23 μM. NVC-422 does not cause any cytotoxicity at concentrations as high as 250 μM. Invitro, NVC-422 inactivates Ad5 but does not interfere with viral replication, indicating that NVC-422 acts on the extracellular adenovirus as a virucidal agent. NVC-422 inactivates Ad5 by oxidative inactivation of key viral proteins such as fiber and hexon as evidenced by SDS-PAGE, Western blotting and reversed-phase HPLC. These data, combined with measurements of the kinetics of the NVC-422 reactivity with selected amino acids, indicate that the changes in the viral proteins are caused by the selective oxidation of sulfur-containing amino acids. The conformational changes of the viral proteins result in the destruction of the viral morphology as shown by transmission electron microscopy. In summary, NVC-422 exhibits virucidal activity against Ad5 by the oxidative inactivation of key viral proteins, leading to the loss of viral integrity and infectivity.
NovaBay Pharmaceuticals, Inc., Emeryville, CA 94608, USA.
Jungjoo
J
Yoon
Andreas
A
Jekle
Ramin
R
Najafi
Francis
F
Ruado
Meghan
M
Zuck
Behzad
B
Khosrovi
Bahram
B
Memarzadeh
Dmitri
D
Debabov
Lu
L
Wang
Mark
M
Anderson
D000258:Adenovirus Infections, Human / Q000188:drug therapy; D000260:Adenoviruses, Human / Q000187:drug effects* / Q000648:ultrastructure; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003236:Conjunctivitis, Viral / Q000188:drug therapy; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D008715:Methionine / Q000737:chemistry; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013654:Taurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014764:Viral Proteins / Q000737:chemistry; D038301:Virus Inactivation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D013438:Sulfhydryl Compounds; D014764:Viral Proteins; D013654:Taurine; D008715:Methionine; C560851:NVC-422; D003545:Cysteine