title: De Novo Design of Skin-Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs.
abstract: Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents.
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Menegatti
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zakrewsky
authors.affiliation: Nitto Denko, Oceanside, CA, 92058, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Joshua Sanchez
authors.initials: JS
authors.lastname: De Oliveira
authors.affiliation: Convoy Therapeutics, Oro Valley, AZ, 85704, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Muraski
authors.affiliation: Center for Bioengineering, Department of Chemical Engineering, University of California, Santa Barbara, CA, 93106, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000595:Amino Acid Sequence; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D000078404:Epidermal Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D007633:Keratins / Q000378:metabolism; D013058:Mass Spectrometry; D019151:Peptide Library; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012867:Skin / Q000187:drug effects*; D012869:Skin Absorption / Q000187:drug effects*; D013816:Thermodynamics
chemical_list: D019151:Peptide Library; D010455:Peptides; D004364:Pharmaceutical Preparations; D007633:Keratins; D016572:Cyclosporine
keywords: cyclosporine A; de novo peptide design; keratin; skin-penetrating peptides; transdermal delivery