Daily Respiratory Research Analysis
Analyzed 76 papers and selected 3 impactful papers.
Summary
Structural biology delineates design rules for pan-coronavirus 3CL protease inhibitors across alpha-, beta-, and gamma-coronaviruses. Clinical genetics strengthens the disease-gene association of LAMP3 in interstitial lung disease with functional validation, while a large prospective cohort links prenatal PFAS exposure to elevated risk of childhood respiratory allergic diseases, highlighting environmental prevention targets.
Research Themes
- Structure-guided antiviral drug design for coronaviruses
- Genetic mechanisms of pediatric interstitial lung disease
- Environmental exposures and childhood respiratory allergy risk
Selected Articles
1. Structural basis for pan-coronavirus inhibition of 3CL protease.
High-resolution crystal structures of two broad-spectrum inhibitors bound to 3CL proteases from six α/β/γ coronaviruses define conserved interaction principles across S1–S4 subsites. The work maps residue-dependent variability (notably in S2 and S4) and provides concrete design rules for pan-coronavirus inhibitor optimization.
Impact: It delivers a comparative structural blueprint enabling truly broad-spectrum coronavirus protease inhibition, a high-priority goal for pandemic preparedness.
Clinical Implications: While preclinical, the defined S1–S4 interaction rules can accelerate structure-guided medicinal chemistry to develop pan-coronavirus antivirals resilient to sequence diversity, informing candidate selection for clinical trials.
Key Findings
- Determined high-resolution X-ray structures of two inhibitors bound to 3CLpro from six α-, β-, and γ-coronaviruses.
- Identified design principles: polar anchoring in S1, hydrophobic packing in S2, compact S3, and mid-sized hydrophobic S4 substitutions.
- Showed S2 interactions depend on three key residues, and S4 variability can be accommodated by solvent exposure of divergent side chains.
Methodological Strengths
- Comparative crystallography across multiple coronavirus genera with high-resolution complexes.
- Structure-activity mapping of subsite-specific interactions (S1–S4) enabling generalizable design rules.
Limitations
- Preclinical structural work without in vivo efficacy or resistance evolution testing.
- Biophysical snapshots do not capture dynamic protease-inhibitor kinetics in cellular contexts.
Future Directions: Leverage subsite rules to optimize chemotypes, evaluate breadth against emergent CoVs, test antiviral potency and resistance barriers in cell/animal models, and advance candidates to phase 1 trials.
Epidemic and pandemic outbreaks of respiratory illness caused by three different coronaviruses over the past two decades have underscored the importance of pharmaceutical agents that could offer broad-spectrum activity across this family of pathogens. Two coronavirus inhibitors characterized by broad in vitro potency were synthesized and studied with X-ray crystallography. Their high-resolution structures in complex with six α-, β-, and γ-coronaviruses delineate the requirements for pan-coronavirus inhibition by drug-like molecules targeting the S1-S4 subsites of the viral 3CL-protease, which performs a critical function during coronavirus polyprotein processing. Anchoring by polar contacts in S1, utilization of hydrophobic packing in S2, compact substitutions in S3, and mid-sized hydrophobic modifications in S4 are all factors contributing to inhibitor activity. Interactions in S2 are modulated by the amino acid identity of three key residues, and in S4, where sequence conservation is the lowest, pan-coronavirus coverage is facilitated by solvent exposure of the diverging side chains.
2. Biallelic LAMP3 Variants in Five Families with Interstitial Lung Disease: Evidence of a Disease-Gene Association.
Across five families (13 individuals), biallelic LAMP3 variants produced variable chILD phenotypes, with early-life ground-glass opacities progressing to fibrosis in symptomatic cases. Functional assays showed reduced LAMP3 expression and abnormal glycosylation, supporting LAMP3 as a disease gene for interstitial lung disease.
Impact: This study consolidates clinical and functional evidence that LAMP3 deficiency underlies a subset of childhood interstitial lung disease, informing diagnosis and genetic counseling.
Clinical Implications: Include LAMP3 in genetic testing panels for unexplained ILD across ages; anticipate ground-glass opacities and potential progression to fibrosis; consider surfactant biology assessment (BAL, biopsy) in select cases.
Key Findings
- Identified 13 individuals with biallelic LAMP3 variants across five families with ILD.
- Symptomatic individuals showed early ground-glass opacities and later lung fibrosis; one case had abnormal BAL surfactant composition and irregular lamellar bodies.
- In vitro expression of specific LAMP3 variants led to reduced protein expression and abnormal glycosylation in lung epithelial cells.
Methodological Strengths
- Integrated clinical phenotyping with BAL/biopsy data and molecular functional assays.
- Use of multiple orthogonal techniques (IHC, Western blot, flow cytometry) to validate variant effects.
Limitations
- Small sample size and potential ascertainment bias across families.
- In vitro overexpression systems may not fully recapitulate in vivo AT2 cell biology.
Future Directions: Establish genotype-phenotype correlations, develop in vivo models to probe surfactant trafficking, and explore targeted therapies correcting protein processing.
PURPOSE: Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease (chILD). Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of chILD. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants. METHODS: Phenotypic data was collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, WB, and flow cytometry. RESULTS: Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For one participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular LB. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation. CONCLUSIONS: Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.
3. Prenatal PFAS exposure and childhood respiratory allergic diseases: Findings from Shanghai Birth cohort Consortium.
In 4,166 mother–child pairs, doubling of maternal PFOA levels was associated with higher odds of childhood respiratory allergic diseases (aOR 1.21), with similar effects for the summed carboxylate PFAS. The PFAS–RAD association appeared stronger under higher prenatal particulate exposure, indicating potential co-exposure synergy.
Impact: This prospective biomonitoring study quantifies prenatal PFAS associations with childhood respiratory allergy and suggests modification by air pollution, informing environmental health policy and prevention strategies.
Clinical Implications: Clinicians can counsel pregnant patients on minimizing PFAS exposure sources and support policies reducing PFAS and particulate matter; pediatric risk stratification may consider prenatal exposure profiles.
Key Findings
- Among 4,166 pairs, 23.9% of children had respiratory allergic diseases by age <8 years.
- Maternal PFOA median was 11.97 ng/mL (PFOS 9.68 ng/mL); doubling of PFOA was associated with higher RAD odds (aOR 1.21, 95% CI 1.03–1.41).
- The molar sum of five carboxylate PFAS (∑PFCAs) was also associated with increased RAD risk (aOR 1.21, 95% CI 1.03–1.42), with stronger associations observed under higher prenatal particulate exposure.
Methodological Strengths
- Population-based prospective design with LC-MS/MS quantification of multiple PFAS in early pregnancy.
- Adjusted generalized linear models and assessment of mixture effects and effect modification by co-exposures.
Limitations
- Potential residual confounding and exposure misclassification inherent to observational studies.
- RAD outcomes derived from records/questionnaires and incomplete reporting on particulate measurement specifics.
Future Directions: Replicate in diverse populations, refine joint exposure models (PFAS and PM), and elucidate immunologic mechanisms linking prenatal PFAS to airway allergy.
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) pose significant health risks to vulnerable populations such as pregnant women and children. Evidence on prenatal PFAS exposure and childhood respiratory allergic diseases (RAD) is scarce, particularly regarding how this relationship might be modified by prenatal PM OBJECTIVE: To assess the association between prenatal PFAS exposure and the risk of childhood RAD and evaluate whether prenatal PM METHODS: We conducted a population-based prospective cohort study of 4,166 mother-child pairs from the Shanghai Birth Cohort Consortium to investigate this relationship. Data on RAD (including asthma and allergic rhinitis) in children under 8 years of age were collected from medical records or validated questionnaires. Concentrations of seven PFAS were measured in maternal blood collected during early pregnancy using ultra-high performance liquid chromatography/triple quadrupole tandem mass spectrometry. Generalized linear regression models were used to assess the associations between PFAS and childhood RAD after adjusting for potential confounders. RESULTS: Among the participants, 1,003 (23.9%) children were diagnosed with RAD. PFOA exhibited the highest median concentration (11.97 ng/mL), followed by PFOS (9.68 ng/mL). A doubling increment in PFOA was associated with an increased adjusted odds ratio (aOR) for childhood RAD (1.21, 95% CI: 1.03 to 1.41). The molar sum of five carboxylate PFAS (∑PFCAs) were also significantly associated with elevated RAD risk (aOR = 1.21, 95% CI: 1.03 to 1.42). Additionally, we observed that higher prenatal PM CONCLUSION: Prenatal exposure to individual and PFAS mixture was associated with an increased risk of childhood RAD, particularly allergic rhinitis. Children born to mothers with high PM