Proteomic Network Analysis of Bronchoalveolar Lavage Fluid in Ex-Smokers to Discover Implicated Protein Targets and Novel Drug Treatments for Chronic Obstructive Pulmonary Disease
Abstract
Bronchoalveolar lavage of the epithelial lining fluid (BALF) can sample the profound changes in the airway lumen milieu prevalent in chronic obstructive pulmonary disease (COPD). We compared the BALF proteome of ex-smokers with moderate COPD who are not in exacerbation status to non-smoking healthy control subjects and applied proteome-scale translational bioinformatics approaches to identify potential therapeutic protein targets and drugs that modulate these proteins for the treatment of COPD. Proteomic profiles of BALF were obtained from (1) never-smoker control subjects with normal lung function (n = 10) or (2) individuals with stable moderate (GOLD stage 2, FEV1 50–80% predicted, FEV1/FVC 1800 proteins identified in the BALF were significantly differentially expressed in COPD versus control. Functional annotation of the differentially expressed proteins was used to detail canonical pathways containing the differential expressed proteins. Topological network analysis demonstrated that four putative proteins act as central node proteins in COPD. The drugs with the most similar interaction signatures to approved COPD drugs were extracted with the CANDO platform. The drugs identified using CANDO were subsequently analyzed using a knowledge-based technique to determine an optimal two-drug combination that had the most appropriate effect on the central node proteins. Network analysis of the BALF proteome identified critical targets that have critical roles in modulating COPD pathogenesis, for which we identified several drugs that could be repurposed to treat COPD using a multiscale shotgun drug discovery approach.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2022
- Source ID
- 10.3390/ph15050566
Entities
People
- Chengjian Tu
- Gordon Broderick
- Jun Qu
- Manoj J Mammen
- Matthew C Morris
- Ram Samudrala
- Sanjay Sethi
- Spencer Richman
- William Mangione
- Zackary Falls
Organizations
- American Heart Association
- Congressionally Directed Medical Research Programs
- National Institutes of Health