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Inhibitors for Spt4\/Spt5 using peptides as a starting point for assays as a means for developing small molecules, which could likely lead to therapeutic development for inhibition for Spt4\/Spt5 with CNS characteristics. To elucidate the specific steps of identification and modification of key interacting residues from Spt4\/Spt5 complex with further effect prediction, a set of different computational methods was applied. Newly characterized, theoretically derived peptides docked on Spt4\/Spt5 models, based on X\u2010ray crystallography sources, allowed us to complete molecular dynamics simulations and docking studies for peptide libraries that give us high confident set of peptides for use to screen for Spt4\/Spt5 inhibition. Several peptides with increased specificity to the Spt4\/Spt5 interface were found and can be screened in cell\u2010based assays and enzymatic assays for peptide screens that lead to small molecule campaigns. Spt4\/Spt5 comprises an attractive target for neurological diseases, and applying these peptides into a screening campaign will promote the goal of therapeutic searches for FTD drug discovery.<\/jats:p>","DOI":"10.1002\/jcb.29820","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T15:50:28Z","timestamp":1594050628000},"page":"4922-4930","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Peptidyl inhibition of Spt4\u2010Spt5: Protein\u2010protein inhibitors for targeting the transcriptional pathway related to C9orf72 expansion repeats"],"prefix":"10.1002","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7596-6294","authenticated-orcid":false,"given":"Alexey","family":"Rayevsky","sequence":"first","affiliation":[{"name":"Enamine Ltd.  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