An RNA Aptamer Targets the PDZ-Binding Motif of the HPV16 E6 Oncoprotein

Belyaeva, Tamara A.; Nicol, Clare; Cesur, Özlem; Travé, Gilles; Blair, G. Eric; Stonehouse, Nicola J.

doi:10.3390/cancers6031553

Cited by 24 publications

(17 citation statements)

References 46 publications

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“…Belyaeva et al reported two RNA aptamers to E6, named F2 and F4, which induced apoptosis in cells derived from an HPV16-transformed cervical carcinoma. This aptamers were able to inhibit the interaction between E6 and PDZ1 from Magi1, with F2 being the most effective inhibitor, while none of them inhibited E6–p53 interaction or p53 degradation [121]. …”

Section: Aptamers For Virus Diagnosis and Treatmentmentioning

confidence: 99%

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

González

Martı́n

Fernández³

et al. 2016

Pharmaceuticals

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Appropriate diagnosis is the key factor for treatment of viral diseases. Time is the most important factor in rapidly developing and epidemiologically dangerous diseases, such as influenza, Ebola and SARS. Chronic viral diseases such as HIV-1 or HCV are asymptomatic or oligosymptomatic and the therapeutic success mainly depends on early detection of the infective agent. Over the last years, aptamer technology has been used in a wide range of diagnostic and therapeutic applications and, concretely, several strategies are currently being explored using aptamers against virus proteins. From a diagnostics point of view, aptamers are being designed as a bio-recognition element in diagnostic systems to detect viral proteins either in the blood (serum or plasma) or into infected cells. Another potential use of aptamers is for therapeutics of viral infections, interfering in the interaction between the virus and the host using aptamers targeting host-cell matrix receptors, or attacking the virus intracellularly, targeting proteins implicated in the viral replication cycle. In this paper, we review how aptamers working against viral proteins are discovered, with a focus on recent advances that improve the aptamers’ properties as a real tool for viral infection detection and treatment.

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Section: Aptamers For Virus Diagnosis and Treatmentmentioning

confidence: 99%

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

González

Martı́n

Fernández³

et al. 2016

Pharmaceuticals

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“…exceeds the C eff value observed for another dimeric ligand targeting the PSD-95 protein (100-fold affinity increase, C eff % 100 mm). [19] Being built from fragments of two proteins targeted by all hrm-HPV E6 proteins,t he chimera proved to be au niversal ligand for hrm-HPV E6 proteins.T his is as trong advantage over previously published E6 ligands,i ncluding small molecules, [20] antibodies, [21] peptides, [22] and RNAa ptamers, [23] which were all developed to target only one particular E6 protein (HPV16 E6). Since E6 is ah allmark of all HPVpositive tumors,the chimera can serve as adiagnostic tool for E6 capture followed by immunodetection, as demonstrated here (Figure 3e).…”

Section: Methodsmentioning

confidence: 99%

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High‐Affinity Bivalent Ligand

et al. 2015

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The E6 oncoproteins of high-risk mucosal (hrm) human papillomaviruses (HPVs) contain ap ocket that captures LxxLL motifs and aC-terminal motif that recruits PDZ domains,w ith both functions being crucial for HPV-induced oncogenesis.Achimeric protein was built by fusing aP DZ domain and an LxxLL motif,b oth knownt ob ind E6. NMR spectroscopy, calorimetry and am ammalian protein complementation assayc onverged to showt hat the resulting PDZLxxLL chimera is abivalent nanomolar ligand of E6, while its separated PDZ and LxxLL components are only micromolar binders.The chimera binds to all of the hrm-HPV E6 proteins tested but not to low-risk mucosal or cutaneous HPV E6. Adenovirus-mediated expression of the chimera specifically induces the death of HPV-positive cells,c oncomitant with increased levels of the tumour suppressor P53, its transcriptional target p21, and the apoptosis marker cleaved caspase 3. The bifunctional PDZ-LxxLL chimera opens new perspectives for the diagnosis and treatment of HPV-induced cancers.Papillomaviruses (PVs) infect the cutaneous and mucosal epithelia of vertebrates.[1] Whereas most PVs are benign, asubset of "high-risk" mucosal human PV types (hrm-HPVs) induce cervical cancer [2] and as ignificant proportion of head and neck cancers.[3] HPV 16 is the most prevalent and best studied hrm-HPV type.H PV carcinogenesis is primarily linked to two PV oncoproteins,E 6a nd E7.[4] hrm-HPV E6 recruits the ubiquitin ligase E6AP and the tumour suppressor P53, which leads to ubiquitin-mediated degradation of P53. [5] This dramatically reduces P53 protein levels in HPV-infected cells,t hereby disrupting the pro-apoptotic and genome watchdog functions of P53. In this process,E 6b inds within E6AP an acidic leucine-rich motif containing an LxxLL consensus sequence.[6] TheX-ray crystallography structure of the E6/E6AP complex has shown that E6 captures the motif within ac onserved basic-hydrophobicp ocket.[7] Hrm-HPV E6 also binds to and sometimes promotes the degradation of several PDZ-containing cellular proteins,w hich regulate cell-cell adhesion, cell polarity,a nd apoptosis. Hrm-HPV E6 captures PDZ domains by means of as hort PDZ binding motif (PBM), which is situated at the extreme Cterminus of E6.[8] Several structures of E6/PDZ complexes have been solved [9] . E6 thus possesses two interaction surfaces responsible for its two best-described oncogenic activities.W ee xploited our recent structural insights into both activities [7, 9a] to build ah eterobivalent E6-binding construct to simultaneously target both interaction surfaces.W ed esigned ac himeric PDZ-LxxLL fusion protein ( Figure S1 in the Supporting Information) comprising the MAGI1 PDZ2 domain (the second of the six PDZ domains of MAGI1, sometimes named "PDZ1" or "PDZ2/6" in earlier works), [9a] at hree-alanine linker,and the E6-binding LxxLL motif of E6AP (sequence: ELTLQELLGEER).[7] By combining our previous structures of the E6/LxxLL complex (PDB ID 4GIZ [7] ;F igure 1a)a nd of the E6/PDZ2 complex (PDB ID 2KPL[9a] ;F igure...

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“…The aptamer interaction with PDZ domain was very specific and the interaction between E6 and p53 was not affected [53]. The same research group also isolated RNA aptamers against E7 oncoprotein that were able to disturb the E7-pRb interaction by targeting E7 for degradation and showed that one of them (A2) was able to inhibit cellular proliferation by inducing apoptosis in SiHa cervical carcinoma cells [54].…”

Section: Aptamers Against Hpvmentioning

confidence: 99%

Application of Nucleic Acid Aptamers to Viral Detection and Inhibition

Leija-Montoya¹,

Benítez‐Hess²,

Álvarez-Salas³

2016

Nucleic Acids - From Basic Aspects to Laboratory Tools

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Nucleic acid aptamers are small oligonucleotides that specifically bind to other molecules through noncovalent interactions that rely on complex tridimensional structural arrangements. Aptamers are generated through the iterative in vitro selection method called SE-LEX, resulting in specific binding against a wide variety of molecular targets including viruses. Because aptamers are obtained in vitro and can be synthetically produced, they have been envisioned as future diagnostic and therapeutic tools for human diseases including virus-borne pathologies. Aptamers have been isolated against a number of viruses including pandemic influenza virus, human papillomavirus and hepatitis C virus. Although aptamers have proven themselves as extremely sensitive detection tools triggering the development of affordable and highly diagnostic methods, their use as therapeutic moieties has been hampered by biostability, delivery and pharmacodynamical issues. Nevertheless, a new generation of chemically modified aptamers shows promise for the coming of age of protein-targeted noncatalytic oligonucleotides for the therapy of viral disease. The present review focuses on the most successful antiviral aptamers reported and includes a description of some of the novel methods developed for their use as diagnostic and therapeutic tools

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An RNA Aptamer Targets the PDZ-Binding Motif of the HPV16 E6 Oncoprotein

Cited by 24 publications

References 46 publications

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

Use of Aptamers as Diagnostics Tools and Antiviral Agents for Human Viruses

Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High‐Affinity Bivalent Ligand

Application of Nucleic Acid Aptamers to Viral Detection and Inhibition

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