Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations.

BACKGROUND: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. OBJECTIVE: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe-host interactions modify risk of asthma exacerbation in a season-specific manner. METHODS: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. RESULTS: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). CONCLUSIONS: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria-host interactions that significantly increase risk of asthma exacerbation in these children.

The oral microbiome: Role of key organisms and complex networks in oral health and disease.

States of oral health and disease reflect the compositional and functional capacities of, as well as the interspecies interactions within, the oral microbiota. The oral cavity exists as a highly dynamic microbial environment that harbors many distinct substrata and microenvironments that house diverse microbial communities. Specific to the oral cavity, the nonshedding dental surfaces facilitate the development of highly complex polymicrobial biofilm communities, characterized not only by the distinct microbes comprising them, but cumulatively by their activities. Adding to this complexity, the oral cavity faces near-constant environmental challenges, including those from host diet, salivary flow, masticatory forces, and introduction of exogenous microbes. The composition of the oral microbiome is shaped throughout life by factors including host genetics, maternal transmission, as well as environmental factors, such as dietary habits, oral hygiene practice, medications, and systemic factors. This dynamic ecosystem presents opportunities for oral microbial dysbiosis and the development of dental and periodontal diseases. The application of both in vitro and culture-independent approaches has broadened the mechanistic understandings of complex polymicrobial communities within the oral cavity, as well as the environmental, local, and systemic underpinnings that influence the dynamics of the oral microbiome. Here, we review the present knowledge and current understanding of microbial communities within the oral cavity and the influences and challenges upon this system that encourage homeostasis or provoke microbiome perturbation, and thus contribute to states of oral health or disease.