Airway ciliary dysfunction and respiratory symptoms in patients with transposition of the great arteries

<div><p>Background</p><p>Our prior work on congenital heart disease (CHD) with heterotaxy, a birth defect involving randomized left-right patterning, has shown an association of a high prevalence of airway ciliary dysfunction (CD; 18/43 or 42%) with increased respiratory symptoms. Furthermore, heterotaxy patients with ciliary dysfunction were shown to have more postsurgical pulmonary morbidities. These findings are likely a reflection of the common role of motile cilia in both airway clearance and left-right patterning. As CHD comprising transposition of the great arteries (TGA) is commonly thought to involve disturbance of left-right patterning, especially L-TGA with left-right ventricular inversion, we hypothesize CHD patients with transposition of great arteries (TGA) may have high prevalence of airway CD with increased respiratory symptoms.</p><p>Methods and results</p><p>We recruited 75 CHD patients with isolated TGA, 28% L and 72% D-TGA. Patients were assessed using two tests typically used for evaluating airway ciliary dysfunction in patients with primary ciliary dyskinesia (PCD), a recessive sinopulmonary disease caused by respiratory ciliary dysfunction. This entailed the measurement of nasal nitric oxide (nNO), which is typically low with PCD. We also obtained nasal scrapes and conducted videomicroscopy to assess respiratory ciliary motion (CM). We observed low nNO in 29% of the patients, and abnormal CM in 57%, with 22% showing both low nNO and abnormal CM. No difference was observed for the prevalence of either low nNO or abnormal ciliary motion between patients with D vs. L-TGA. Respiratory symptoms were increased with abnormal CM, but not low nNO. Sequencing analysis showed no compound heterozygous or homozygous mutations in 39 genes known to cause PCD, nor in CFTR, gene causing cystic fibrosis. As both are recessive disorders, these results indicate TGA patients with ciliary dysfunction do not have PCD or cystic fibrosis (which can cause low nNO or abnormal ciliary motion).</p><p>Conclusions</p><p>TGA patients have high prevalence of abnormal CM and low nNO, but ciliary dysfunction was not correlated with TGA type. Differing from PCD, respiratory symptoms were increased with abnormal CM, but not low nNO. Together with the negative findings from exome sequencing analysis, this would suggest TGA patients with ciliary dysfunction do not have PCD but nevertheless may suffer from milder airway clearance deficiency. Further studies are needed to investigate whether such ciliary dysfunction is associated with increased postsurgical complications as previously observed in CHD patients with heterotaxy.</p></div

Multivariable regression analysis of respiratory symptoms in TGA patients>6 Yr.

<p>Multivariable regression analysis of respiratory symptoms in TGA patients>6 Yr.</p

Univariable regression analysis of respiratory symptoms in TGA patients>6 Yr.

<p>Univariable regression analysis of respiratory symptoms in TGA patients>6 Yr.</p

Analysis of incidence of PCD gene mutations in TGA cohort.

<p>Analysis of incidence of PCD gene mutations in TGA cohort.</p

Nasal NO measurements in TGA patients.

<p>Nasal NO measurements in TGA patients.</p

Abnormal CM and low NO prevalence with D vs. L-TGA.

<p>Abnormal CM and low NO prevalence with D vs. L-TGA.</p

Summary of TGA patients assessed for both ciliary motion abnormalities and low nNO levels.

<p>Shown in the flowchart are 75 TGA patients with ciliary motion available in 67 and nNO values available on 50 patients, broken down into normal and abnormal within each type of TGA.</p

Increased respiratory symptoms in TGA patients >6 yrs of age with abnormal ciliary motion and low nNO.

<p>Increased respiratory symptoms in TGA patients >6 yrs of age with abnormal ciliary motion and low nNO.</p

Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 (<b>3</b>) was identified as a promising lead with cross-pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of <b>3</b> incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)­aniline substituent. We report the biological activity of these inhibitors against <i>Trypanosoma brucei</i> (HAT), <i>T. cruzi</i> (Chagas disease), and <i>Leishmania major</i> (cutaneous leishmaniasis) and describe the identification of <i>N</i>-(5-chloropyrimidin-2-yl)-6-(4-(morpholinosulfonyl)­phenyl)­quinolin-4-amine (<b>13t</b>) as a promising inhibitor of <i>L. major</i> proliferation and 6-(4-(morpholinosulfonyl)­phenyl)-<i>N</i>-(pyrimidin-4-yl)­quinolin-4-amine (<b>13j</b>), a potent inhibitor of <i>T. brucei</i> proliferation with improved drug-like properties

Antitrypanosomal Lead Discovery: Identification of a Ligand-Efficient Inhibitor of Trypanosoma cruzi CYP51 and Parasite Growth

Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi, and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure–activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds <b>4c</b> (NEU321) and <b>4j</b> (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of <b>4c</b> and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of <b>4c</b> to that of other, previously reported inhibitors. We show that <b>4c</b> displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization