Abstract
The limitations of current therapies for human cytomegalovirus (HCMV) coupled with the continued impact of HCMV disease in the immunocompromised host are the driving force for the development of new drugs against HCMV. This review predominantly focuses on new non-DNA polymerase inhibitors of HCMV replication. Drugs such as tomeglovir (BAY-384766), 2-bromo-5,6-dichloro-1- β-D-ribofuranosyl benzimidazole (BDCRB) and GW-275175X act as inhibitors of the terminase complex that is involved in cleavage and packaging of the unit length DNA into the capsids. Although the viral protein kinase UL97 has been exploited as an activator of ganciclovir and its prodrug valganciclovir, a new inhibitor maribavir (benzamidavir) has been shown to be a highly potent inhibitor of this enzyme. Many of these compounds have undergone successful phase I clinical trials. There are other compounds which have been identified through drug-screening but are at the earlier stages of development.
Similar content being viewed by others
References
Griffiths PD, Emery VC. Cytomegalovirus. In: Richman DD, Whitley RJ, Hayden FG, editors. Clinical Virology. New York: Churchill Livingstone, 1997: 445–70
Pillay D, Emery VC, Griffiths PD. Clinical aspects of treatment of cytomegalovirus. In: Jeffries DJ, DeClerq E, editors. Antiviral Chemotherapy. Chichester: Wileys, 1995: 265–83
Emery V, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Natl Acad Sci U S A 2000; 97: 8039–44
Lowance D, Neumayer HH, Legendre C, et al. Valaciclovir reduces the incidence of cytomegalovirus disease and acute rejection in renal allograft recipients. N Engl J Med 1999; 340: 1462–70
Brown F, Banken L, Saywell K, et al. Pharmacokinetic of valganciclovir and follwoing multiple dosages of valganciclovir in HIV- and CMV- seropositive volunteers. Clin Pharmacokinet 1999; 37: 167–76
Pescovitz MD, Rabkin J, Merion RM, et al. Vlaganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 2000; 44(10): 2811–5
Sugawara M, Huang W, Fei YJ, et al. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci 2000; 89(6): 781–9
Razonable RR, Rivero A, Rodriguez A, et al. Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J Infect Dis 2001; 184(11): 1461–4
Boivin G, Gilbert C, Gaudreau A, et al. Rate of emergence of cytomegalovirus (CMV) mutations in leukocytes of patients with acquired immunodeficiency syndrome who are receiving valganciclovir as induction and maintenance therapy for CMV retinitis. J Infect Dis 2001; 184(12): 1598–602
Underwood MR, Harvey RJ, Stanat S, et al. Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 Gene Product. J Virol 1998; 72: 717–25
Krosky PM, Underwood MR, Turk SR, et al. Resistance of human cytomegalovirus to benzimidazole ribonucleosides maps to two open reading frames: UL89 and UL56. J Virol 1998; 72: 4721–8
Boyd F, Turner EM Freeman GA, et al. Synthesis and evaluation of a series of 1H-benzimidazole pyranosides as anti-human cytomegalovirus agents. Proceedings of the 218th ACS National Meeting; 1999 Aug 22–26; New Orleans (LA), USA
Chulay J, Biron KK, Wang L, et al. Development of novel benzimidazole riboside compounds for treatment cytomegalovirus disease. Adv Exp Med Biol 1999; 458: 129–34
Zacny VL, Gershburg E, Davis MG, et al. Inhibition of Epstein-Barr virus replication by a benzimidazole L-riboside: novel antiviral mechanism of 5, 6-dichloro-2-(isopropylamino)- 1-beta-L-ribofuranosyl-1H benzamidazole. J Virol 1999; 73: 7271–7
Littler E, Stuart AD, Chee MS. Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature 1992; 358: 160–2
Eckenberg P, Reefschlaeger J, Bender W, et al. Structure-activity-relationships of BAY 38-4766 — a novel non-nucleosidic inhibitor of human cytomegalovirus replication [abstract no. 940]. Proceedings of the 39th ICAAC; 1999 Sep 26–29; San Francisco
Reefschlaeger J, Bender W, Eckenberg P, et al. Antiviral activity and selectivity of BAY 38-4766 — a novel non-nucleosidic inhibitor of human cytomegalovirus replication [abstract no. 942]. Proceedings of the 39th ICAAC; 1999 Sep 26–29; San Francisco
Hallenberger S, Trappe J, Buerger I, et al. Mechanism of antiviral action of BAY 38-4766 — a novel non-nucleosidic inhibitor of human cytomegalovirus replication [abstract no. 941]. Proceedings of the 39th ICAAC; 1999 Sep 26–29; San Francisco
Kern A, Blombach M, Schmeer K, et al. In vivo metabolism in rat and dog of BAY 38-4766 — a novel non-nucleosidic inhibitor of human cytomegalovirus replication [abstract no. 943]. Proceedings of the 39th ICAAC; 1999 Sep 26–29; San Francisco
Nagelschmitz J, Moeller JG, Stass H, et al. Safety, tolerability and pharmacokinetics of single oral doses of BAY 38-4766 — a novel, non-nucleosidic inhibitor of human cytomegalovirus (HCMV) replication — in healthy male subjects [abstract no. 945]. Proceedings of the 39th ICAAC; 1999 Sep 26–29; San Francisco
Oien NL, Hopkins TA, Poorman RA, et al. Selective inhibition of herpesvirus DNA polymerases by novel 4-hydroxyquinolines [abstract no. 1855]. Proceedings of the 40th ICAAC; 2000 Sep 17–20; Toronto
Martinez A, Esteban AI, Castro A, et al. Novel potential agents for human cytomegalovirus infection: synthesis and antiviral activity evaluation of benzothiadiazine acyclonucleosides. J Med Chem 1999; 42: 1145–50
Martinez A, Gil C, Perez C, et al. Benzothiadiazine dioxide dibenzyl derivatives as potent human cytomegalovirus inhibitors: synthesis and comparative molecular field analysis. J Med Chem 2000; 43: 3218–25
Martinez A, Gil C, Perez C, et al. Nonnucleoside human cytomegalovirus inhibitors: synthesis and antiviral evaluation of (chlorophenylmethyl) benzothiadiazine dioxide derivatives. J Med Chem 2000; 43: 3267–73
Vara Prasad JVN, Steinbaugh B, Booth R, et al. Tricyclic compounds as non-nucleoside inhibitors of human simplex virus replication in vitro [abstract no. 768]. Proceedings of the 40th ICAAC; 2000 Sep 17–20; Toronto
Meyer AL, Bruening EE, Dunkle WE, et al. PD0084430: A non-nucleoside inhibitor of human cytomegalovirus replication in vitro [abstract no. 785]. Proceedings of the 40th ICAAC; 2000 Sep 17–20; Toronto
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Emery, V.C., Hassan-Walker, A.F. Focus on New Drugs in Development Against Human Cytomegalovirus. Drugs 62, 1853–1858 (2002). https://doi.org/10.2165/00003495-200262130-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200262130-00002