Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

Rationale The primary rescue medication to treat acute asthma exacerbation is short-acting β2- adrenergic receptor (β2AR) agonists (SABAs), however there is variation in how well an individual responds to treatment. Although these differences may be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator drug response (BDR). Methods We performed a genome-wide association study (GWAS) for BDR in 1,782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified seven genetic variants associated with BDR at a genome-wide significant threshold (p<5×10−8), all of which had frequencies below 5%. Furthermore, we observed an excess of small p-values driven by rare variants (frequency < 5%), and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified five significant peaks; fine mapping within these peaks identified two rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in solute carrier genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multi-ethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.

Therapeutic, III.

The transporter protein Large-neutral Amino Acid Transporter 1 (LAT-1, SLC7A5) is responsible for transporting amino acids such as tyrosine and phenylalanine as well as thyroid hormones, and it has been exploited as a drug delivery mechanism. Recently its role in cancer has become increasingly appreciated, as it has been found to be up-regulated in many different tumor types, and its expression levels have been correlated with prognosis. Substitution at the meta position of aromatic amino acids has been reported to increase affinity for LAT-1; however, the SAR for this position has not previously been explored. Guided by newly refined computational models of the binding site, we hypothesized that groups capable of filling a hydrophobic pocket would increase binding to LAT-1, resulting in improved substrates relative to parent amino acid. Tyrosine and phenylalanine analogs substituted at the meta position with halogens, alkyl and aryl groups were synthesized and tested in cis-inhibition and trans-stimulation cell assays to determine activity. Contrary to our initial hypothesis we found that lipophilicity was correlated with diminished substrate activity and increased inhibition of the transporter. The synthesis and SAR of meta-substituted phenylalanine and tyrosine analogs is described.

Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden.

Background: As early as 2022, United States Medical Licensing Examination Step 1 results will be reported as pass or fail, rather than as 3-digit numeric scores. This survey examines the perspectives of plastic surgery applicants and program directors (PD) regarding this score reporting change. Methods: A 24-item survey was distributed to integrated applicants from the 2018–19 and 2019–20 application cycles. An analogous 28-item survey was sent to integrated and independent plastic surgery training program directors. Data were analyzed using summary tables and marginal homogeneity tests. Results: 164 applicants (33.2%) and 64 PDs (62.1%) completed the survey. Most applicants (60.3%) and PDs (81.0%) were not in favor of the score reporting change. As a result of binary scoring, a majority of respondents anticipate that residency programs will use Step 2 CK scores to screen applicants (applicants: 95.7%, PDs: 82.8%), prioritize students from more prestigious medical schools (applicants: 91.5%, PDs: 52.4%), and that dedicated research time will become more important (applicants: 87.9%, PDs: 45.3%). Most applicants (66.4%) and PDs (53.1%) believe that there will be an increase in plastic surgery applicants. Applicants and PDs anticipate that the top 3 metrics used by programs when deciding to offer an interview will change as a result of binary Step 1 scoring. Conclusions: Most plastic surgery applicants and PDs do not support the change in United States Medical Licensing Examination Step 1 scoring to pass or fail. The majority believe that other metrics (such as Step 2 CK scores, research experience, and medical school reputation) will become more important in the application process.

Large neutral amino acid transporter 1 (LAT1) is a solute carrier protein located primarily in the blood-brain barrier (BBB) that offers the potential to deliver drugs to the brain. It is also up-regulated in cancer cells, as part of a tumor’s increased metabolic demands. Previously, amino acid prodrugs have been shown to be transported by LAT1. Carboxylic acid bioisosteres may afford prodrugs with an altered physicochemical and pharmacokinetic profile than those derived from natural amino acids, allowing for higher brain or tumor levels of drug and/or lower toxicity. The effect of replacing phenylalanine’s carboxylic acid with a tetrazole, acylsulfonamide and hydroxamic acid (HA) bioisostere was examined. Compounds were tested for their ability to be LAT1 substrates using both cis-inhibition and trans-stimulation cell assays. As HA-Phe demonstrated weak substrate activity, its structure-activity relationship (SAR) was further explored by synthesis and testing of HA derivatives of other LAT1 amino acid substrates (i.e. Tyr, Leu, Ile, and Met). The potential for a false positive in the trans-stimulation assay caused by parent amino acid was evaluated by conducting compound stability experiments for both HA-Leu and the corresponding methyl ester derivative. We concluded that HA’s are transported by LAT1. In addition, our results lend support to a recent account that amino acid esters are LAT1 substrates, and that hydrogen bonding may be as important as charge for interaction with the transporter binding site.

Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.