Inhibition of HSV-1 protease by benzoxazinones

Jarvest, Richard L.; Parratt, Martin J.; Debouck, Christine; Gorniak, Joselina G.; Jennings, L. J.; Serafinowska, Halina T.; Strickler, J. Rudi

doi:10.1016/0960-894x(96)00455-6

Cited by 104 publications

(58 citation statements)

References 12 publications

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“…These reactive amino acids provide the opportunity to identify inhibitors that bind covalently to the active site by reacting with the serine hydroxyl group or disulphide bonding with cysteine. Several unique classes of compounds such as thieno [2,3-d]ioxazinones and spirocyclopropyl oxazolones ( Figure 5) have been described as inhibiting the HCMV protease by acylation of the active site serine [69][70][71][72][73]. Benzimidazole sulphoxides ( Figure 5) that inhibit the HCMV protease by reacting with the active site cysteine have also been described [74].…”

Section: Hcmv Protease Inhibitorsmentioning

confidence: 97%

Non‐nucleoside inhibitors of herpesviruses

Wathen¹

2002

Reviews in Medical Virology

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While the treatment of herpes simplex virus with acyclovir and similar nucleoside analogues was one of the first success stories in antiviral chemotherapy, substantial unmet medical needs remain for herpesvirus diseases. In particular, the increasing numbers of immunosuppressed people due to AIDS, transplantation, cancer and aging has driven the need for improved antivirals to treat diseases caused by human cytomegalovirus (HCMV). Currently available drugs for the treatment of HCMV diseases are less than ideal agents due to issues of toxicity, modest efficacy and poor oral bioavailability. High throughput screening of large compound collections for inhibitors of specific viral enzymes or inhibition of viral growth in cell culture have identified a number of new HCMV inhibitors at several pharmaceutical companies. These compounds act by inhibition of novel molecular targets such as the viral protein kinase, viral protease and viral proteins involved in DNA cleavage/packaging. In addition, novel non-nucleoside inhibitors of the herpesvirus DNA polymerase have recently been described. This review will summarise some of these research efforts and will focus on non-nucleoside compounds that directly inhibit a viral process.

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Section: Hcmv Protease Inhibitorsmentioning

confidence: 97%

Non‐nucleoside inhibitors of herpesviruses

Wathen¹

2002

Reviews in Medical Virology

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“…The most potent heterocyclic benzoxazinone inhibitor for HSV-1 protease [111] has an IC 50 of around 5 µM. Subsequently, more potent and selective thienoxazinones, which are structurally related to benzoxazinones, were designed for HSV-1 and HSV-2 protease and had improved Ki in the sub µM range [112].…”

Section: Non-peptidic Inhibitorsmentioning

confidence: 99%

Impact of Recombinant DNA Technology and Protein Engineering on Structure-Based Drug Design: Case Studies of HIV-1 and HCMV Proteases

Kan

2002

CTMC

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Structure-based drug design is an organized, multidisciplinary endeavor undertaken by scientists from many different scientific fields. The success of structure-based drug design was only made possible by advances in structure biology that provides the three-dimensional structure of the drug design target with which small molecular chemical ligands interact. Visualization of the conformation and interactions of a small molecule ligand bound to the protein target in the co-crystal structure of the protein:ligand complex enables the design of new chemical compounds with improved binding affinity and specificity. With the advances in molecular biology, lab automation, and computational science, genomic data have now become available for the human genome, as well as various other organisms. The pharmaceutical industry is currently putting forth tremendous effort in the area of functional genomics and structural genomics in attempts to decipher functions and structures of protein encoded by genes, with the ultimate goal of identifying novel targets for drug discovery and development. This chapter discusses the significant impact made by recombinant DNA technology and protein engineering on structural biology and, more specifically, on structure-based drug design.

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“…107,108 Directed mechanism-based screening, targeted to compounds that could afford a stable acylenzyme adduct of the active site serine, identi®ed a novel class of serine protease inhibitors, the spirocyclopropyl oxazolones represented by 62±64 as submicromolar inhibitors of HCMV protease, 109 and the known serine protease inhibitor class of 2-substituted benzoxazinones. 110,111 A series of 6-substituted 2-aminobenzoxazinone analogs (65±67) has been prepared that show potent inhibitory activity toward the target enzyme (IC 50 0.46±4 mM) and demonstrate antiviral activity in cell culture (IC 50 23 mM). Modi®cations of the substituent at the 6-position modulates both enzyme selectivity and plasma stability without adversely affecting potency toward the viral protease.…”

Section: Hcmv Protease Inhibitorsmentioning

confidence: 99%

Recent strategies in the development of new human cytomegalovirus inhibitors

Martı́nez¹,

Castro²,

Gil³

et al. 2001

Medicinal Research Reviews

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Human cytomegalovirus (HCMV) is one of the most common opportunistic infections in immunucompromised individuals, such as AIDS patients and organ transplant recipients, and is the most frequent congenital viral infection in humans. Despite a reduction of the incidence of AIDS‐related opportunistic infections in patients under highly active antiretroviral treatment, attention should be paid to the HCMV risk factor in these individuals. Furthermore, HCMV may have an important role in atherosclerosis. Existing antiviral treatments for the HCMV infection suffer from poor bioavailability, toxicity, and limited effectiveness, mainly due to the development of drug resistance. Fortunately there are novel and potentially very effective new compounds undergoing pre‐clinical and clinical evaluation. This review provides an overview in the last five years of new HCMV inhibitors (chemical structures, SAR, and new mechanisms of action) with the aim to provide new clues for the development of future drugs against this opportunistic virus. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 227–244, 2001

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Inhibition of HSV-1 protease by benzoxazinones

Cited by 104 publications

References 12 publications

Non‐nucleoside inhibitors of herpesviruses

Non‐nucleoside inhibitors of herpesviruses

Impact of Recombinant DNA Technology and Protein Engineering on Structure-Based Drug Design: Case Studies of HIV-1 and HCMV Proteases

Recent strategies in the development of new human cytomegalovirus inhibitors

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