Daily Respiratory Research Analysis
Three impactful studies in respiratory science span discovery to delivery: (1) an orally available bispecific inhibitor (TMP1) that targets coronavirus Mpro and RdRp, suggesting a path toward broad-spectrum antivirals; (2) a membrane-wide CRISPRa screen identifying druggable host factors (LGMN, KCNA6) that facilitate SARS-CoV-2 entry and shape tissue tropism; and (3) a pediatric network analysis revealing substantial disparities in nirsevimab uptake for RSV prophylaxis, highlighting urgent equit
Summary
Three impactful studies in respiratory science span discovery to delivery: (1) an orally available bispecific inhibitor (TMP1) that targets coronavirus Mpro and RdRp, suggesting a path toward broad-spectrum antivirals; (2) a membrane-wide CRISPRa screen identifying druggable host factors (LGMN, KCNA6) that facilitate SARS-CoV-2 entry and shape tissue tropism; and (3) a pediatric network analysis revealing substantial disparities in nirsevimab uptake for RSV prophylaxis, highlighting urgent equity gaps.
Research Themes
- Broad-spectrum antiviral development for coronaviruses
- Host determinants of SARS-CoV-2 entry and tissue tropism
- Immunization equity and implementation for RSV prevention
Selected Articles
1. An orally available M
This study reports the design of TMP1, an orally available bispecific inhibitor that simultaneously targets coronavirus main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The approach addresses the need for broad-spectrum antivirals against current and future zoonotic coronaviruses.
Impact: A dual-target, orally available antiviral could reduce resistance risk and expand therapeutic breadth across coronaviruses. This represents a mechanistically innovative avenue beyond single-enzyme inhibitors.
Clinical Implications: If validated in vivo and clinically, TMP1 could serve as a pan-coronavirus oral therapy, complementing vaccines and monoclonals and improving outpatient treatment options.
Key Findings
- Engineered an orally available bispecific inhibitor (TMP1) that targets coronavirus Mpro and RdRp simultaneously.
- Positions a broad-spectrum small-molecule strategy to prepare for future zoonotic coronavirus spillovers.
Methodological Strengths
- Rational multitarget inhibitor design focused on two conserved replication enzymes (Mpro, RdRp).
- Addresses cross-variant and cross-species therapeutic breadth conceptually.
Limitations
- Abstract does not report in vivo efficacy or pharmacokinetics; translational readiness remains to be demonstrated.
- Safety, resistance barrier, and clinical performance are not yet established.
Future Directions: Advance TMP1 into in vivo efficacy, PK/PD, resistance mapping, and first-in-human trials; evaluate breadth against diverse coronaviruses and synergy with existing antivirals.
2. Membrane-wide screening identifies potential tissue-specific determinants of SARS-CoV-2 tropism.
A membrane-focused CRISPRa screen mapped host entry factors for SARS-CoV-2 and pinpointed LGMN and KCNA6 as druggable determinants of tissue-specific tropism. Endogenous loss and pharmacologic inhibition reduced infection and viral entry, and clinical datasets suggested tissue-level associations.
Impact: Identifying host-entry determinants opens therapeutic avenues beyond spike-focused strategies and informs tissue tropism and pathogenesis. The druggability of LGMN/KCNA6 enables repurposing/inhibitor development.
Clinical Implications: Existing or novel inhibitors of LGMN/KCNA6 could be evaluated as host-directed antivirals to reduce entry and mitigate multi-organ involvement, complementing variant-agnostic strategies.
Key Findings
- Membrane-wide CRISPRa screening identified LGMN and KCNA6 as facilitators of SARS-CoV-2 entry.
- Replication-competent virus validation and orthogonal knockdown showed that disrupting endogenous LGMN or KCNA6 reduces infection.
- Pharmacologic inhibition of candidate factors decreased viral entry; clinical datasets supported tissue-level associations.
Methodological Strengths
- Focused CRISPRa library targeting human membrane proteins with ACE2-stratified screens.
- Validation with replication-competent virus, orthogonal gene disruption, and small-molecule inhibition plus clinical data analyses.
Limitations
- Overexpression-based CRISPRa may identify factors that are context dependent; in vivo validation is not reported in the abstract.
- Clinical associations are suggestive and require prospective validation.
Future Directions: Define tissue-specific expression thresholds and in vivo relevance; test selective inhibitors and assess combination with spike-directed antivirals or vaccines.
3. Disparities in Nirsevimab Uptake Across a Pediatric Primary Care Network.
Among 7,208 eligible infants in a 32-practice network, only 35% received nirsevimab, with wide site-level variation (20–65%). Older age, Black race, very low Child Opportunity Index, and public insurance independently predicted lower receipt.
Impact: Immediate, actionable disparities in RSV immunoprophylaxis uptake are identified in real-world care, informing targeted quality improvement and policy interventions.
Clinical Implications: Health systems should implement targeted outreach and access strategies (eg, default ordering at birth, navigation for publicly insured families, culturally tailored communication) to raise equitable RSV protection.
Key Findings
- Only 35% (2,534/7,208) of eligible infants received nirsevimab despite near-universal availability; practice-level uptake ranged 20–65%.
- Lower uptake was independently associated with older age (OR 0.60 per month), Black race (OR 0.53 vs White), very low COI (OR 0.70 vs very high), and public insurance (OR 0.79 vs private).
Methodological Strengths
- Large, diverse primary care network cohort with near-universal product availability minimizes supply-side confounding.
- Multivariable logistic regression quantifies independent associations across demographic and socioeconomic factors.
Limitations
- Observational design may be subject to residual confounding (eg, parental preferences, staff workflows).
- Single network; generalizability to other regions and seasons requires confirmation.
Future Directions: Test targeted interventions (eg, opt-out models, equity dashboards, navigator programs) in pragmatic trials to close uptake gaps; monitor impact on RSV hospitalizations.