De Novo Design of Skin‐Penetrating Peptides for Enhanced Transdermal Delivery of Peptide Drugs. Issue 5 (22nd January 2016)

• Record Type: Journal Article
• Authors: Menegatti, Stefano; Zakrewsky, Michael; Kumar, Sunny; De Oliveira, Joshua Sanchez; Muraski, John A.; Mitragotri, Samir
• Is Part Of: Advanced healthcare materials. Volume 5:Issue 5(2016)
• Page Start: 602
• Page End: 609
• Publication Date: 2016-01-22
• Subjects: cyclosporine A -- de novo peptide design -- keratin -- skin‐penetrating peptides -- transdermal delivery; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.201500634
• Languages: English
• ISSNs: 2192-2640

Abstract

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. Abstract : A computational method is proposed for identifying skin‐penetrating peptides (SPPs) enabling transdermal delivery of therapeutics. The method hinges on the identification of peptide sequences capable of interacting with both keratin and the drug of interest. This approach, validated for the delivery of cyclosporine A, represents an effective procedure for the de novo design of SPPs for delivering therapeutic or personal care products.