# Project 2: PK/PD requirements for mucolytic therapeutic agents in vitro and in vivo

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $478,046

## Abstract

Project 2 has focused on the hypotheses that: (1) hyperconcentrated (dehydrated) mucus produces airway
mucus adhesion/plaques that drive the progression of muco-obstructive lung diseases; and, (2) that clearance
of these plugs/plaques will be therapeutically useful in patients with the muco-obstructive phenotype. Recent
data have indicated that once mucostasis has occurred, modification of mucus plaques may occur that make
them “permanent” and resistant to rehydration therapies. Our biophysical analyses suggest that mucin
molecular weight (MW) reduction will be effective in clearing mucus in this setting without rehydration. Further,
Project 2 hypothesizes that by the generation of disease specific models, that effectively mimic the
extracellular mucins/mucus targets of our disease populations, will produce useful information to guide the
clinical projects with respect to selection of drug doses, dosing frequency, requirement for an active vehicle
(e.g., hypertonic saline) and generate data on “off target” redox effects. In collaboration with tPPG
investigators, we have established that in CF (and COPD) MUC5B is the dominant mucin obstructing airways.
In contrast, we have identified that MUC5AC is the dominant airway mucin in subjects with asthma.
Accordingly, we have generated appropriate cell culture, small animal, and sheep models that mimic the mucin
dominance phenotype for each disease entity. Utilizing these tools, Project 2 will measure and compare the
pharmacodynamics and pharmacokinetic properties of two different, but complementary, thiol reducing agent
clinical candidates. P2176 is a di-thiol compound with rapid reductive activity (Kcat) whereas the mono-thiol
P2114 has a slower intrinsic reductive (Kcat) activity. Both molecules share features designed to retain the
molecules on the airway surface and both molecules have their thiols “capped” by acetate groups that are
cleaved by esterases on airway surfaces to liberate active compounds. The relative effectiveness/properties of
each molecule will be tested in: (1) in vitro HBE cultures designed to mimic the extracellular MUC5AC/MUC5B
ratios of CF/COPD (Il-1β treated) and asthma (IL-13 treated); (2) mouse models of CF/COPD (βENaC) mice,
and asthma (house dust mite treated) to measure clearance of mucus plugs after aerosol drug delivery; and,
large animal sheep models, including wild-type, Ascaris suum exposed, and HNE/CF172 treated sheep to
measure pharmacodynamics and pharmacokinetic parameters. Based on these data, and GLP toxicology
studies, a lead molecule doses/dosing frequency, and a vehicle will be selected. Importantly, Project 2 will also
utilize information gained from Project 1/Project 2 studies and clinical Projects 3 and 4 to study backup
compounds as improvements in the frontrunner become identified/implemented in the parent thiol compound
chassis. Thus the overarching goal of the 2b Project is to identify the optimal drug properties, balancing rate of
mucin thiol reducti...

## Key facts

- **NIH application ID:** 10001600
- **Project number:** 5P01HL108808-09
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Richard Charles Boucher
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $478,046
- **Award type:** 5
- **Project period:** 2017-09-07 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001600

## Citation

> US National Institutes of Health, RePORTER application 10001600, Project 2: PK/PD requirements for mucolytic therapeutic agents in vitro and in vivo (5P01HL108808-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001600. Licensed CC0.

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