{"doi":"10.1016/j.jtos.2020.11.001","title":"Herpes Simplex Virus-1 infection in human primary corneal epithelial cells is blocked by a stapled peptide that targets processive DNA synthesis","abstract":"PURPOSE: 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.","journal":"The Ocular Surface","year":2020,"id":87790,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":445792,"name":"Manunya Nuth","orcid":"0000-0002-3457-8201","position":1,"is_corresponding":false},{"id":445793,"name":"Vivian Lee","orcid":"0000-0002-4470-0143","position":2,"is_corresponding":false},{"id":446524,"name":"Chenyan Lin","orcid":null,"position":3,"is_corresponding":false},{"id":445794,"name":"Claire H. Mitchell","orcid":"0000-0002-9784-6672","position":4,"is_corresponding":false},{"id":446525,"name":"Wennan Lu","orcid":null,"position":5,"is_corresponding":false},{"id":446526,"name":"Richard W. Scott","orcid":null,"position":6,"is_corresponding":false},{"id":445795,"name":"Michael H. Parker","orcid":"0000-0002-3170-3505","position":7,"is_corresponding":false},{"id":362163,"name":"John L. Kulp","orcid":"0000-0003-2586-9207","position":8,"is_corresponding":false},{"id":378072,"name":"Allen B. Reitz","orcid":"0000-0003-2780-4044","position":9,"is_corresponding":false},{"id":445796,"name":"Robert P. Ricciardi","orcid":"0000-0002-2206-3657","position":10,"is_corresponding":false},{"id":446523,"name":"Hancheng Guan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T22:00:29.831859Z","pmid":"33161128","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}