New anti-viral drugs for the treatment of the common cold.
Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 trisubstituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of pi-pi interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 microM, respectively), with the latter exhibiting an ID(50) (dose that inhibits 50% of the viral cytopathic effect) on HRV-14=25 microg/ml.
Maugeri
Caterina
C
Angelini Farmaceutici, A.C.R.A.F. SpA, P.le della Stazione snc, 00040 S. Palomba, Roma, Italy. c.maugeri@angelini.it
Alisi
Maria A
MA
Apicella
Claudia
C
Cellai
Luciano
L
Dragone
Patrizia
P
Fioravanzo
Elena
E
Florio
Saverio
S
Furlotti
Guido
G
Mangano
Giorgina
G
Ombrato
Rosella
R
Luisi
Renzo
R
Pompei
Raffaello
R
Rincicotti
Vito
V
Russo
Vincenzo
V
Vitiello
Marco
M
Cazzolla
Nicola
N
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D003139:Common Cold / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D012229:Rhinovirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*
D000998:Antiviral Agents; D001549:Benzamides; D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases