Discovery, validation, and prodrug design of an ACE2 activator for treating bacterial infection-induced lung inflammation

Lu, Peng; Leslie, Faith; Wang, Han; Sodhi, Anjali; Choi, Chang-yong; Pekosz, Andrew; Cui, Honggang; Jia, Hongpeng

doi:10.1016/j.jconrel.2023.10.025

Cited by 2 publications

(1 citation statement)

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“…Supramolecular peptide–drug conjugates (sPDCs) are a class of drug delivery materials that have shown promising preclinical results in their application to the delivery of a number of small molecule pharmaceutical agents. − Emerging from robust literature on peptide gelators for drug delivery and tissue engineering, − sPDCs are most directly inspired by the peptide amphiphile (PA) molecular design . sPDCs typically include a small molecule prodrug as a hydrophobic block attached to a more hydrophilic and (typically) β-sheet-forming peptide to yield an amphiphilic molecular design; the prodrug motif promotes hydrophobic association of the resulting amphiphilic molecules in aqueous environments and contributes to the self-assembly of precise nanostructures .…”

Section: Introductionmentioning

confidence: 99%

Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates

Sis,

Liu,

Allen

et al. 2024

Biomacromolecules

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Supramolecular peptide−drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and sitespecific delivery of therapeutic agents using a discrete, singlecomponent molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impacts of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug−produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug−alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels as well as their drug release profiles showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials.

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