Herpes Simplex Virus-1 Infection in Human Primary Corneal Epithelial Cells is Blocked by a Stapled Peptide that Targets Processive DNA Synthesis

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dc.contributor.authorGuan, Hancheng
dc.contributor.authorNuth, Nanunya
dc.contributor.authorLee, Vivian
dc.contributor.authorLin, Chenyan
dc.contributor.authorMitchell, Claire H.
dc.contributor.authorLu, Wennan
dc.contributor.authorScott, Richard W.
dc.contributor.authorParker, Michael H.
dc.contributor.authorKulp, John L.
dc.contributor.authorReitz, Allen B.
dc.contributor.authorRicciardi, Robert P.
dc.date2023-05-18T02:55:06.000
dc.date.accessioned2023-05-22T13:17:32Z
dc.date.available2023-05-22T13:17:32Z
dc.date.issued2021-01-01
dc.date.submitted2022-06-30T07:26:14-07:00
dc.description.abstractPurpose: Acyclovir is most commonly used for treating ocular Herpes Keratitis, a leading cause of infectious blindness. However, emerging resistance to Acyclovir resulting from mutations in the thymidine kinase gene of Herpes Simplex Virus −1 (HSV-1), has prompted the need for new therapeutics directed against a different viral protein. One novel target is the HSV-1 Processivity Factor which is essential for tethering HSV-1 Polymerase to the viral genome to enable long-chain DNA synthesis. Methods: A series of peptides, based on the crystal structure of the C-terminus of HSV-1 Polymerase, were constructed with hydrocarbon staples to retain their alpha-helical conformation. The stapled peptides were tested for blocking both HSV-1 DNA synthesis and infection. The most effective peptide was further optimized by replacing its negative N-terminus with two hydrophobic valine residues. This di-valine stapled peptide was tested for inhibiting HSV-1 infection of human primary corneal epithelial cells. Results: The stapled peptides blocked HSV-1 DNA synthesis and HSV-1 infection. The unstapled control peptide had no inhibitory effects. Specificity of the stapled peptides was confirmed by their inabilities to block infection by an unrelated virus. Significantly, the optimized di-valine stapled peptide effectively blocked HSV-1 infection in human primary corneal epithelial cells with selectivity index of 11.6. Conclusions: Hydrocarbon stapled peptides that simulate the α-helix from the C-terminus of HSV-1 DNA polymerase can specifically block DNA synthesis and infection of HSV-1 in human primary corneal epithelial cells. These stapled peptides provide a foundation for developing a topical therapeutic for treating human ocular Herpes Keratitis. © 2020
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/9281
dc.legacy.articleid1519
dc.legacy.fields10.1016/j.jtos.2020.11.001
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1519&context=dental_papers&unstamped=1
dc.source.beginpage313
dc.source.endpage321
dc.source.issue536
dc.source.journalDepartmental Papers (Dental)
dc.source.journaltitleOcular Surface
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume19
dc.subject.otherDNA polymerase
dc.subject.otherHerpes keratitis
dc.subject.otherHerpes simplex virus-1
dc.subject.otherHydrocarbon stapled peptide
dc.subject.otherProcessivity factor
dc.subject.otherDNA
dc.subject.otherEpithelial Cells
dc.subject.otherHerpesvirus 1
dc.subject.otherHuman
dc.subject.otherHumans
dc.subject.otherKeratitis
dc.subject.otherHerpetic
dc.subject.otherPeptides
dc.subject.otheraciclovir
dc.subject.otherDNA polymerase
dc.subject.othergenomic DNA
dc.subject.otherlactate dehydrogenase
dc.subject.otherpeptide
dc.subject.otherrecombinant protein
dc.subject.othervaline
dc.subject.othervirus DNA
dc.subject.otherDNA
dc.subject.otherpeptide
dc.subject.otherabsorption
dc.subject.otheralpha helix
dc.subject.otheramino acid substitution
dc.subject.otheramino terminal sequence
dc.subject.otherArticle
dc.subject.othercarboxy terminal sequence
dc.subject.othercell adhesion
dc.subject.othercell viability
dc.subject.othercontrolled study
dc.subject.othercornea epithelium
dc.subject.othercrystal structure
dc.subject.otherDNA replication
dc.subject.otherDNA synthesis
dc.subject.otherdrug potency
dc.subject.otherenzyme linked immunosorbent assay
dc.subject.otherepithelium cell
dc.subject.otherherpes simplex
dc.subject.otherherpes simplex keratitis
dc.subject.otherhuman
dc.subject.otherHuman alphaherpesvirus 1
dc.subject.otherhuman cell
dc.subject.otherhydrogen bond
dc.subject.otherhydrophobicity
dc.subject.otherin vitro study
dc.subject.othernonhuman
dc.subject.otherprotein conformation
dc.subject.otherprotein cross linking
dc.subject.otherprotein protein interaction
dc.subject.otherreticulocyte lysate
dc.subject.otherselectivity index
dc.subject.othersolvation
dc.subject.otherVaccinia virus
dc.subject.otherVero cell line
dc.subject.othervirus replication
dc.subject.otherepithelium cell
dc.subject.othergenetics
dc.subject.otherherpes simplex keratitis
dc.subject.otherDentistry
dc.titleHerpes Simplex Virus-1 Infection in Human Primary Corneal Epithelial Cells is Blocked by a Stapled Peptide that Targets Processive DNA Synthesis
dc.typeArticle
digcom.contributor.authorGuan, Hancheng
digcom.contributor.authorNuth, Nanunya
digcom.contributor.authorLee, Vivian
digcom.contributor.authorLin, Chenyan
digcom.contributor.authorMitchell, Claire H.
digcom.contributor.authorLu, Wennan
digcom.contributor.authorScott, Richard W.
digcom.contributor.authorParker, Michael H.
digcom.contributor.authorKulp, John L.
digcom.contributor.authorReitz, Allen B.
digcom.contributor.authorRicciardi, Robert P.
digcom.identifierdental_papers/536
digcom.identifier.contextkey29986787
digcom.identifier.submissionpathdental_papers/536
digcom.typearticle
dspace.entity.typePublication
upenn.schoolDepartmentCenterDepartmental Papers (Dental)
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