Publications by authors named "Carly K Schissel"

Peptide-mediated delivery of macromolecules in cells has significant potential therapeutic benefits, but no therapy employing cell-penetrating peptides (CPPs) has reached the market after 30 years of investigation due to challenges in the discovery of new, more efficient sequences. Here, we demonstrate a method for in-cell penetration selection-mass spectrometry (in-cell PS-MS) to discover peptides from a synthetic library capable of delivering macromolecule cargo to the cytosol. This method was inspired by recent selection approaches for cell-surface screening, with an added spatial dimension resulting from subcellular fractionation.

View Article and Find Full Text PDF
Article Synopsis
  • * A new automated fast-flow technology enables the efficient production of CPP-conjugated PNAs (PPNAs), making the synthesis process quick and effective.
  • * The study showed that a PPNA targeting SARS-CoV-2 significantly reduced the virus's presence, indicating potential for developing PPNAs as antiviral therapies.
View Article and Find Full Text PDF

The natural product himastatin has an unusual homodimeric structure that presents a substantial synthetic challenge. We report the concise total synthesis of himastatin from readily accessible precursors, incorporating a final-stage dimerization strategy that was inspired by a detailed consideration of the compound's biogenesis. Combining this approach with a modular synthesis enabled expedient access to more than a dozen designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.

View Article and Find Full Text PDF

Cell-penetrating peptides (CPPs) can cross the cell membrane to enter the cytosol and deliver otherwise nonpenetrant macromolecules such as proteins and oligonucleotides. For example, recent clinical trials have shown that a CPP attached to phosphorodiamidate morpholino oligomers (PMOs) resulted in higher muscle concentration, increased exon skipping, and dystrophin production relative to another study of the PMO alone in patients of Duchenne muscular dystrophy. Therefore, effective design and the study of CPPs could help enhance therapies for difficult-to-treat diseases.

View Article and Find Full Text PDF

Therapeutic macromolecules such as proteins and oligonucleotides can be highly efficacious but are often limited to extracellular targets due to the cell's impermeable membrane. Cell-penetrating peptides (CPPs) are able to deliver such macromolecules into cells, but limited structure-activity relationships and inconsistent literature reports make it difficult to design effective CPPs for a given cargo. For example, polyarginine motifs are common in CPPs, promoting cell uptake at the expense of systemic toxicity.

View Article and Find Full Text PDF

Dysregulation of the transcription factor MYC is involved in many human cancers. The dimeric transcription factor complexes of MYC/MAX and MAX/MAX activate or inhibit, respectively, gene transcription upon binding to the same enhancer box DNA. Targeting these complexes in cancer is a long-standing challenge.

View Article and Find Full Text PDF

When displayed on erythrocytes, peptides and proteins can drive antigen-specific immune tolerance. Here, we investigated a straightforward approach based on erythrocyte binding to promote antigen-specific tolerance to both peptides and proteins. We first identified a robust erythrocyte-binding ligand.

View Article and Find Full Text PDF

There are more amino acid permutations within a 40-residue sequence than atoms on Earth. This vast chemical search space hinders the use of human learning to design functional polymers. Here we show how machine learning enables the de novo design of abiotic nuclear-targeting miniproteins to traffic antisense oligomers to the nucleus of cells.

View Article and Find Full Text PDF

Transcription factors (TF), such as Myc, are proteins implicated in disease pathogenesis, with dysregulation of Myc expression in 50% of all human cancers. Still, targeting Myc remains a challenge due to the lack of small molecule binding pockets in the tertiary structure. Here, we report synthetic covalently linked TF mimetics that inhibit oncogenic Myc-driven transcription by antagonistic binding of the target DNA-binding site.

View Article and Find Full Text PDF

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer.

View Article and Find Full Text PDF

Capture and release of peptides is often a critical operation in the pathway to discovering materials with novel functions. However, the best methods for efficient capture impede facile release. To overcome this challenge, we report linkers based on secondary amino alcohols for the release of peptides after capture.

View Article and Find Full Text PDF

Phosphorodiamidate morpholino oligonucleotides (PMOs) make up a promising class of therapeutics for genetic disease. PMOs designed for "exon skipping" must be internalized into cells, reach the nucleus, and act on pre-mRNA to mediate their effects. One tactic for improving PMO delivery and exon skipping is to covalently conjugate PMOs to cell-penetrating peptides (CPPs).

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Warning

Message: fopen(/var/lib/php/sessions/ci_sessionner97cvebsbsrcrcfq5rgju6a2vn0ga0): Failed to open stream: No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 177

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

A PHP Error was encountered

Severity: Warning

Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)

Filename: Session/Session.php

Line Number: 137

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once