Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease.
Herpes simplex virus infections are the cause of significant morbidity, and currently used therapeutics are largely based on modified nucleoside analogs that inhibit viral DNA polymerase function. To target this disease in a new way, we have identified and optimized selective thiazolylphenyl-containing inhibitors of the herpes simplex virus (HSV) helicase-primase enzyme. The most potent compounds inhibited the helicase, the primase and the DNA-dependent ATPase activities of the enzyme with IC50 (50% inhibitory concentration) values less than 100 nM. Inhibition of the enzymatic activities was through stabilization of the interaction between the helicase-primase and DNA substrates, preventing the progression through helicase or primase catalytic cycles. Helicase-primase inhibitors also prevented viral replication as demonstrated in viral growth assays. One compound, BILS 179 BS, displayed an EC50 (effective concentration inhibiting viral growth by 50%) of 27 nM against viral growth with a selectivity index greater than 2,000. Antiviral activity was also demonstrated for multiple strains of HSV, including strains resistant to nucleoside-based therapies. Most importantly, BILS 179 BS was orally active against HSV infections in murine models of HSV-1 and HSV-2 disease and more effective than acyclovir when the treatment frequency per day was reduced or when initiation of treatment was delayed up to 65 hours after infection. These studies validate the use of helicase-primase inhibitors for the treatment of acute herpesvirus infections and provide new lead compounds for optimization and design of superior anti-HSV agents.
Crute
James J
JJ
Research and Development Center, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA. jim_crute@aurorabio.com
Grygon
Christine A
CA
Hargrave
Karl D
KD
Simoneau
Bruno
B
Faucher
Anne-Marie
AM
Bolger
Gordon
G
Kibler
Philip
P
Liuzzi
Michel
M
Cordingley
Michael G
MG
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000627:therapeutic use*; D004265:DNA Helicases / Q000037:antagonists & inhibitors*; D019915:DNA Primase; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy / Q000201:enzymology; D006561:Herpes Simplex / Q000188:drug therapy* / Q000201:enzymology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D011725:Pyridines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D014764:Viral Proteins
D000998:Antiviral Agents; C453220:BILS 179 BS; D004791:Enzyme Inhibitors; D011725:Pyridines; D013844:Thiazoles; D014764:Viral Proteins; D019915:DNA Primase; C062021:helicase-primase, Human herpesvirus 1; D004265:DNA Helicases