Herpes simplex virus types I and 2 cause lifelong latent infections. Reactivation of virus gives recurrent infections that are especially problematic in immunocompromised patients. Virus shedding during subclinical recurrences may infect sex partners or newborns. Herpes simplex encephalitis is a continuing source of morbidity and neurological sequelae in newborns and adults. We have established that inhibitors of the HSV thymidine kinase (TK) prevent recurrent infections in animal models. In phase I we developed a convenient synthetic method to prepare our lead drug candidate, g-(4- hydroxybutyl)-N2-phenylguanine (HBPG), and related compounds. We established a dose-dependent reduction in ocular HSV1 reactivation in mice, and found that a single dose of drug was sufficient for this purpose. We participated in analysis of the x-ray crystal structure of HBPG:HSV1 TK complex, and have begun using the structure for rational drug design. We prepared a candidate prodrug of HBPG, and demonstrated its rapid conversion in plasma in vitro to the ultimate drug. We will pursue the following aims during phase II. 1. Prepare large quantities of HBPG and related inhibitors for animal studies. 2. Use molecular modelling to predict new, potent inhibitors of HSV1 and HSV2 TK. 3. Synthesize and study pharmacokinetic properties in mice of prodrugs of HBPG, with emphasis on increasing oral bioavailabilty. 4. Compare efficacy of HBPG with newer compounds and prodrugs in latent mouse HSV1 models and an optimized candidate in the squirrel monkey model. 5. Determine efficacy of HBPG and a prodrug against HSV1 encephalitis in mice, alone and with other antivirals.
Drugs that prevent reactivation of Herpes simplex viruses from latency will be of value in treating immunocompromised patients and patients with antiviral drug-resistant infections, and can prevent virus shedding and transmission. Drugs that reduce the morbidity of HSV encephalitis and neonatal herpes infections will have great benefit in these poorly managed diseases.
| Lossani, Andrea; Savi, Lida; Manikowski, Andrzej et al. (2012) N(2)-Phenyl-9-(hydroxyalkyl)guanines and related compounds are substrates for Herpes simplex virus thymidine kinases. J Mol Biochem 1:21-25 |
| Manikowski, Andrzej; Verri, Annalisa; Lossani, Andrea et al. (2005) Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo. J Med Chem 48:3919-29 |
