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Kinetic Analysis of Cellular Internalization and Expulsion of Unstructured D-chirality Cell Penetrating Peptides
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  • Manibarathi Vaithiyanathan,
  • Hannah Hymel,
  • Nora Safa,
  • Olivia Sanchez,
  • Jacob Pettigrew,
  • Cole Kirkpatrick,
  • Ted Gauthier,
  • Adam Melvin
Manibarathi Vaithiyanathan
Louisiana State University System
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Hannah Hymel
Louisiana State University System
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Nora Safa
Louisiana State University System
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Olivia Sanchez
Louisiana State University System
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Jacob Pettigrew
Louisiana State University System
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Cole Kirkpatrick
Louisiana State University System
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Ted Gauthier
LSU Agricultural Center
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Adam Melvin
Louisiana State University System
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Abstract

Most cell penetrating peptides (CPPs) are unstructured and susceptible to proteolytic degradation. One alternative is to incorporate D-chirality amino acids into unstructured CPPs to allow for enhanced uptake and intracellular stability. This work investigates CPP internalization using a series of time, concentration, temperature, and energy dependent studies, resulting in a three-fold increase in uptake and 50-fold increase in stability of D-chirality peptides over L-chirality counterparts. CPP internalization occurred via a combination of direct penetration and endocytosis, with a percentage of internalized CPP expelling from cells in a time-dependent manner. Mechanistic studies identified that cells exported the intact internalized D-chirality CPPs via an exocytosis independent pathway, analogous to a direct penetration method out of the cells. These findings highlight the potential of D-chirality CPPs as bio-vectors in therapeutic and biosensing applications, but also identify a new expulsion method suggesting a relationship between uptake kinetics, intracellular stability, and export kinetics

Peer review status:UNDER REVIEW

07 Apr 2020Submitted to AIChE Journal
14 Apr 2020Submission Checks Completed
14 Apr 2020Assigned to Editor
16 Apr 2020Reviewer(s) Assigned
18 May 2020Editorial Decision: Revise Major
19 Jun 20201st Revision Received
25 Jun 2020Submission Checks Completed
25 Jun 2020Assigned to Editor
26 Jun 2020Reviewer(s) Assigned
20 Jul 2020Editorial Decision: Revise Major
03 Sep 20202nd Revision Received
11 Sep 2020Submission Checks Completed
11 Sep 2020Assigned to Editor
14 Sep 2020Reviewer(s) Assigned