Structure Elucidation of the First Inhibitors of Human Papillomavirus Type 11 E1E2 ProteinProtein Interaction

Abstract

A novel series of inhibitors of the HPV11 E1ÀE2 proteinÀprotein interaction was identified. These inhibitors, which were discovered as a result of high-throughput screening, feature an indandione system spirofused onto an appropriately substituted tetrahydrofuran ring. Early stability studies indicated, surprisingly, that this particular series of compounds were readily converted, in binding assay buffer, to the corresponding carboxylates. NMR and mass spectrometry techniques were used to elucidate the structures of these products and the mechanism by which they are produced.Introduction. ± There are more than 100 human papillomavirus (HPV) types, associated with a broad spectrum of disease ranging from cutaneous and genital warts to anogenital cancer. Each of these different HPV types infects specific tissues and is responsible for particular pathologies. For example, HPV1 infections cause plantar warts on the feet, HPV6 and 11 cause genital warts, and HPV16 is the major cause of cervical cancer [1].The HPV genome encodes eight well-characterized proteins, only one of which, the E1 helicase, has enzymatic activity. The others either serve structural roles or are involved in interactions with host-cell factors [2]. In addition to E1, only one other viral protein, E2, is required for replication of the genome [3] [4]. Viral-DNA replication is initiated by the cooperative binding of E1 and E2 to the HPV origin. Assembly of this E1ÀE2Àorigin ( E1ÀE2Àori) complex is dependent on the binding of E2 to highaffinity sites in the origin as well as on a critical proteinÀprotein interaction between E1 and E2 [5] [6]. E1 and E2 also recruit to the origin host-cell proteins required for replication, including the polymerase a primase [7].Currently, genital warts are treated by a variety of ablative and cytodestructive therapies including the use of liquid nitrogen or trichloroacetic acid or by topical administration of the immunostimulator imiquimod [8]. These treatments are far from ideal, and there clearly remains a need for specific inhibitors of viral replication. The essential proteins E1 and E2 are attractive targets for such antiviral chemotherapy [9].Recently, we described a series of compounds that inhibit the cooperative binding of E1 and E2 to the viral origin of replication [10] [11]. These inhibitors, which were discovered as a result of high-throughput screening, feature an indandione system

Crystal Structure of the E2 Transactivation Domain of Human Papillomavirus Type 11 Bound to a Protein Interaction Inhibitor

“…The data shown (absorbance at 280 nm versus radius (r 2 /2, cm 2 )) were obtained at 30,000 rpm, 20°C. The initial TAD concentration was ϳ4 M. The line corresponds to the fit obtained from data at all runs in Table II structure of the free carboxylate form confirms a prediction that this form is the one with inhibitory activity (43).…”

“…The two inhibitor 1 molecules are both in the free carboxylate form (as drawn in Fig. 3), one of two distinct forms that this class of inhibitors adopts in solution (43). The presence in the crystal …”

Gold–Ferrocene Glyco‐Nanoparticles for High‐Sensitivity Electrochemical Detection of Carbohydrate–Lectin Interactions

“…In order to study the role of two carbonyl groups on the oxirane, two donor–acceptor oxiranes. 1m with one acetyl group and 1k with two electron‐withdrawing groups in a rigid form which cannot bind to the Lewis acid at the same time, were prepared according to the literature methods 16. When these two donor–acceptor oxiranes were subjected to the reaction conditions, no desired cycloadducts were detected [Eqs.…”

Novel Cycloaddition Reaction of [60]Fullerene with Carbonyl Ylides Generated from Epoxides

“…Epoxides undergoing thermal or photochemical 1,3-dipolar cycloaddition via carbonyl ylides with alkenes, alkynes, benzylidene anilines, thioketones, and phosphaalkynes have been well-documented. Due to the electron-deficient-alkene property of C 60 , we therefore investigated the reaction of C 60 with epoxides.…”