A short description of promising candidates for preventing and treating airway irritation based primarily on reduced sulfur compounds.

1. Regenerating Airway Epithelium
J. Thomas Pierce MBBS PhD
International University of Health Sciences

2. Airway epithelium is in the line of fire…
• Continuously exposed to microorganisms,
dust, tobacco smoke, among hundreds of
entries;
• Natural regeneration depends upon cell
migration, proliferation and differentiation;
• (Histology) Microcirculation determines
degree of fibrin-fibronectin (Fn-Fbn) covering;

3. Suggested Regenerative Components
• Regenerative components includes cytoskeleton
proteins, integrins receptors, matrix
metalloproteinases (MMPs), cytokines (IL-series) and
growth factors (Puchelle et al. 2006).
• Pro-inflammatory cytokines of interest include
• (IL-8) and MMPs (-9 and -7 in particular) - barometers
of dysregulation and remodeling of airway mucosa;
• Airway epithelium literature is vast - solutions will likely
span molecular scaffolds, adapted stem cells, small
molecules and newer biologic therapies.

4. Glutathione Synthesis, Distribution &
Homeostasis Critical to Regeneration
• Glutathione is the body’s major antioxidant
and detoxifier, reducing both upper airway
and lung inflammation (Ziem 2013);
• Synthetic derivatives such as L-γ-glutamyl-2-
methyl-L-cysteinyl-glycine disulfide preferred
in terms of inhibiting glutathione reductase
activity (Kedrowski and Gutow 2013).

5. They all smell bad…
• Glutathione can be used to form a molecular
hydrogel based on glutathione (GSH) reduction
(Lv et al. 2013);
• Another possibility is that of a nanoparticle
delivery vehicle for S-nitroso-N-acetyl cysteine
(Nacharaju et al. 2012).;
• We don’t know whether glutathione or N-acetyl
cysteine or might be best suited;

6. Biomarker possibilities…
• Underlying airway dysfunction somewhat
mirrored by disturbances in transcription of
nuclear factor (erythroid-derived 2)-like 2 (Nrf2);
• Disturbances result in both Nrf2 mRNA and
protein increasing with increased thiol oxidation,
yet the Nrf2 is dysfunctional (Fitzgerald et al.
2012);
• Noted primarily in children c severe asthma
(Fitzgerald 2011, 2012).

7. No heuristic ever tells you all you need
to know, but…
• We like the MLP (multiple lipophilicity
potential) because…
• It relates to individual features of candidate
molecules (‘drug seeds’) as opposed to;
• A single logP value the provides a sort of
grand average, neglecting individual
contributions.

8. MLP
•
• MLPk = Σfi fct (dik)
• Sum over i = 1 to N
•
• MLP = Multiple lipophilicity potential
• k = label for a point on the molecular surface
• i = fragment label
• N = total no. of fragments
• fi = lipophilicity constant for fragment
• fct = distance function
• d ik = distance between fragment i and space point f

9. Thinking about several things at
once – they are all important…
----------------Lipophilicity-----------
log P < 0 log P > 0
<-------------Hydrophobicity------------
-Philic -Phobic
<------------------------Polarity------------------------------ -
Polar Non polar

10. • Recent work by Vallianatou et al. (2015) suggest
an adaptation of ADME-T in favor of what they
term "drug-likeness;"
• They posit that special attention should be paid
to lipophilicity and molecular weight;
• NB: Excessive lipophilicity itself can be associated
with undesired effects.

11. NAC has a History of Poor Acceptance
– Odor and Taste Issues
• Cysteine levels can be WNL when glutathione
concentrations ar, in fact, low (Ziem 2014),
suggesting local effects and differences;
• Oral availability of glutathione (tripeptide) is
low, perhaps suggesting nebulizer use;
• Bishop et al. (2005) pioneered use of inhaled
buffered reduced glutathione for cystic fibrosis
patients.

12. Which one is it...?
• Clinical practice in treating airway irritation sometimes
uses a cocktail approach inclusive of a reduced sulfur
entity plus methyl cobalamine (B12) and tocopherol
(Vitamin E);
• In its role as an anti-oxidant, glutathione must be
protected from its own photo- or heat-based oxidation;
• For neurologic diseases glutathione (and analogues)
have been injected and given intravenously.;

13. Continuous, lifelong irritation –
Prophylaxis or Curative Rx?
• In an older paper, Duan et al. (1996)
considered regional differences in the ability
to supply glutathione;
• How would a drug candidate address the
continuous, progressive nature of injury and
even changes initiated before a therapeutic
regimen commences (Ganesan and Sajjan
2013).