Racial and Ethnic Disparities in Hospital-Based Care Among Dual Eligibles Who Use Health Centers.

Introduction: Health center use may reduce hospital-based care among Medicare-Medicaid dual eligibles, but racial and ethnic disparities in this population have not been widely studied. We examined the extent of racial and ethnic disparities in hospital-based care among duals using health centers and the degree to which disparities occur within or between health centers. Methods: We used 2012-2018 Medicare claims and health center data to model emergency department (ED) visits, observation stays, hospitalizations, and 30-day unplanned returns as a function of race and ethnicity among dual eligibles using health centers. Results: In rural and urban counties, age-eligible Black individuals had more ED visits (7.9 [4.0, 11.7] and 13.7 [10.0, 17.4] per 100 person-years) and were more likely to experience an unplanned return (1.4 [0.4, 2.4] and 1 [0.4, 1.6] percentage points [pp]) than White individuals, but were less likely to be hospitalized (-3.3 [-3.9, -2.8] and -1.2 [-1.6, -0.9] pp). In urban counties, age-eligible Black individuals were 1.2 [0.9, 1.5] pp more likely than White individuals to have observation stays. Other racial and ethnic groups used the same or less hospital-based care than White individuals. Including state and health center fixed effects eliminated Black versus White disparities in all outcomes, except hospitalization. Results were similar among disability-eligible duals. Conclusion: Racial and ethnic disparities in hospital-based care among dual eligibles are less common within than between health centers. If health centers are to play a more central role in eliminating racial and ethnic health disparities, these differences across health centers must be understood and addressed.

Primary care patterns among dual eligibles with Alzheimer's disease and related dementias.

BACKGROUND: Primary care is essential for persons with Alzheimer's disease and related dementias (ADRD). Prior research suggests that the propensity to provide high-quality, continuous primary care varies by provider setting, but the settings used by Medicare-Medicaid dual-eligibles with ADRD have not been described at the population level. METHODS: Using 2012-2018 Medicare data, we identified dual-eligibles with ADRD. For each person-year, we identified primary care visits occurring in six settings. We calculated descriptive statistics for beneficiaries with a majority of visits in each setting, and conducted a k-means cluster analysis to determine utilization patterns, using the standardized count of primary care visits in each setting. RESULTS: Each year from 2012 to 2018, at least 45.6% of dual-eligibles with ADRD received a majority of their primary care in nursing facilities, while at least 25.2% did so in physician offices. Over time, the share relying on nursing facilities for primary care decreased by 5.2 percentage points, offset by growth in Federally Qualified Health Centers (FQHCs) and miscellaneous settings (2.3 percentage points each). Dual-eligibles relying on nursing facilities had more annual primary care visits (16.1) than those relying on other settings (range: 6.8-10.7 visits). Interpersonal care continuity was also higher in nursing facilities (97.0%) and physician offices (87.9%) than in FQHCs (54.2%), rural health clinics (RHCs, 46.6%), or hospital-based clinics (56.8%). Among dual-eligibles without care continuity, 82.7% were assigned to a cluster with few primary care visits. CONCLUSIONS: A trend toward care in different settings likely reflects improved access to patient-centered primary care. Low rates of interpersonal care continuity in FQHCs, RHCs, and physician offices may warrant concern, unless providers in these settings function as a care team. Nonetheless, every healthcare system encounter presents an opportunity to designate a primary care provider for dual-eligibles with ADRD who use little or no primary care.

Characterizing the Uptake of Newly Opened Health Centers by Individuals Dually Enrolled in Medicare and Medicaid.

Federally qualified health centers (FQHCs) increasingly provide high-quality, cost-effective primary care to individuals dually enrolled in Medicare and Medicaid. However, not everyone can access an FQHC. We used 2012 to 2018 Medicare claims and federally collected FQHC data to examine communities where an FQHC first opened and determine which dual eligibles used it. Overall uptake was 10%, ranging from 6.6% among age-eligible urban residents to 14.8% among disability-eligible rural residents. Community-level uptake ranged from 0% to 76.4% (median = 5.5%; interquartile range = 2.8%-11.3%). Certain subpopulations of dual eligibles are significantly more likely to use FQHCs. Our findings should inform the targeting of future FQHC expansions.

The association between primary care use and potentially-preventable hospitalization among dual eligibles age 65 and over.

BACKGROUND: Individuals dually-enrolled in Medicare and Medicaid (dual eligibles) are disproportionately sicker, have higher health care costs, and are hospitalized more often for ambulatory care sensitive conditions (ACSCs) than other Medicare beneficiaries. Primary care may reduce ACSC hospitalizations, but this has not been well studied among dual eligibles. We examined the relationship between primary care and ACSC hospitalization among dual eligibles age 65 and older. METHODS: In this observational study, we used 100% Medicare claims data for dual eligibles ages 65 and over from 2012 to 2018 to estimate the likelihood of ACSC hospitalization as a function of primary care visits and other factors. We used linear probability models stratified by rurality, with subgroup analyses for dual eligibles with diabetes or congestive heart failure. RESULTS: Each additional primary care visit was associated with an 0.05 and 0.09 percentage point decrease in the probability of ACSC hospitalization among urban (95% CI: - 0.059, - 0.044) and rural (95% CI: - 0.10, - 0.08) dual eligibles, respectively. Among dual eligibles with CHF, the relationship was even stronger with decreases of 0.09 percentage points (95% CI: - 0.10, - 0.08) and 0.15 percentage points (95% CI: - 0.17, - 0.13) among urban and rural residents, respectively. CONCLUSIONS: Increased primary care use is associated with lower rates of preventable hospitalizations for dual eligibles age 65 and older, especially for dual eligibles with diabetes and congestive heart failure. In turn, efforts to reduce preventable hospitalizations for this dual-eligible population should consider how to increase access to and use of primary care.

Health center use and hospital-based care among individuals dually enrolled in Medicare and Medicaid, 2012-2018.

OBJECTIVE: To examine the relationship between federally qualified health center (FQHC) use and hospital-based care among individuals dually enrolled in Medicare and Medicaid. DATA SOURCES: Data were obtained from 2012 to 2018 Medicare claims. STUDY DESIGN: We modeled hospital-based care as a function of FQHC use, person-level factors, a Medicare prospective payment system (PPS) indicator, and ZIP code fixed effects. Outcomes included emergency department (ED) visits (overall and nonemergent), observation stays, hospitalizations (overall and for ambulatory care sensitive conditions), and 30-day unplanned returns. We stratified all models on the basis of eligibility and rurality. DATA EXTRACTION METHODS: Our sample included individuals dually enrolled in Medicare and Medicaid for at least two full consecutive years, residing in a primary care service area with an FQHC. We excluded individuals without primary care visits, who died, or had end-stage renal disease. PRINCIPAL FINDINGS: After the Medicare PPS was introduced, FQHC use in rural counties was associated with fewer ED and nonemergent ED visits per 100 person-years among both age-eligible (-14.8 [-17.5, -12.1]; -6.6 [-7.5, -5.6]) and disability-eligible duals (-11.3 [-14.4, -8.3]; -6 [-7.4, -4.6]) as well as a lower probability of observation stays (-0.8 pp age-eligible; -0.4 pp disability-eligible) and unplanned returns (-2.1 pp age-eligible; -1.9 pp disability-eligible). In urban counties, FQHC use was associated with more ED and nonemergent ED visits per 100 person-years (10.6 [8.4, 12.8]; 4.0 [2.6, 5.4]) among disability-eligible duals (a decrease of more than 60% compared with the pre-PPS period) and increases in the probability of hospitalization (1.1 pp age-eligible; 0.8 pp disability-eligible) and ACS hospitalization (0.5 pp age-eligible; 0.3 pp disability-eligible) (a decrease of roughly 50% compared with the pre-PPS period). CONCLUSIONS: FQHC use is associated with reductions in hospital-based care among dual enrollees after introduction of the Medicare PPS. Further research is needed to understand how FQHCs can tailor care to best serve this complex population.

Nursing home care under Medicaid managed long-term services and supports.

OBJECTIVE: To measure the impact of Medicaid managed long-term services and supports (MLTSS) on nursing home (NH) quality and rebalancing. DATA SOURCES/STUDY SETTING: This study analyzes secondary data from annual NH recertification surveys and the minimum dataset (MDS) in three states that implemented MLTSS: Massachusetts (2001-2007), Kansas and Ohio (2011-2017). STUDY DESIGN: We utilized a difference-in-difference approach comparing NHs in border counties of states that implemented MLTSS with a control group of NHs in neighboring border counties in states that did not implement MLTSS. Sensitivity analyses included a triple-difference model (stratified by Medicaid payer mix) and a within-state comparison. We examined changes in six NH-level outcomes (percentage of low-care NH residents, facility occupancy, and four NH quality measures) after MLTSS implementation. DATA COLLECTION/EXTRACTION METHODS: For each state, all freestanding NHs in border counties were included, as were NHs in neighboring counties located in other states. Information on low-care residents was aggregated to the NH level from MDS data, then combined with Online Survey Certification and Reporting (OSCAR) and Certification and Survey Provider Enhanced Reporting (CASPER) data. PRINCIPAL FINDINGS: MLTSS had no statistically significant effects on NH quality outcomes in Massachusetts or Kansas. In Ohio, MLTSS led to an increase of 0.21 nursing hours per resident day [95% CI: 0.03, 0.40], and a decrease of 1.47 deficiencies [95% CI: -2.52, -0.42] and 9.38 deficiency points [95% CI: -18.53, -0.24] per certification survey. After MLTSS, occupancy decreased by 1.52 percentage points [95% CI: -2.92, -0.12] in Massachusetts, but increased by 3.17 percentage points [95% CI: 0.36, 5.99] in Ohio. We found no effect on low-care residents in any state. Findings were moderately sensitive to the choice of comparator group. CONCLUSION: The study provides little evidence that MLTSS reduces quality of care, occupancy, or the percentage of low-care residents in NHs.

Interventions for Health: Why and How Health Care Systems Provide Programs to Benefit Unhoused Patients.

Individuals experiencing homelessness have poorer health than housed individuals, while also utilizing more emergency department care and fewer preventive services. Several interventions - including permanent supportive housing, medical respite, and mobile medical clinics - are cost-effective means to improve health outcomes for homeless populations, yet few health systems have invested in such programs. This study aimed to determine the reasons some health systems initiated these interventions, and the early experience of those health systems that did. Quantitative analyses of health systems in 4 states with high levels of homelessness showed that interventions to improve the health of homeless populations were more common in larger hospitals, teaching hospitals, religious hospitals, network-affiliated hospitals, and hospitals in California. Interviews confirmed that health systems typically were moved to implement these interventions by more than 1 factor, including financial goals, mission-driven motives, a desire to improve care quality, and recognition of local need. Interviewees reported collaborations with community service providers, and some reported targeting services to specific subpopulations. Health systems reported success with some initiatives but noted that success was contingent on overcoming barriers including funding, opposition from the local community, challenges building true partnerships with service providers, and the reluctance of some homeless patients to receive services. Health systems may be encouraged by the results reported by early adopters who navigated these obstacles, while policy makers might consider incentivizing health systems to engage in these interventions by providing a dedicated funding stream.

Care Configurations and Unmet Care Needs in Older Men and Women.

Older adults frequently experience adverse consequences as the result of unmet care needs, including not getting dressed and going without food when hungry. Previous studies have noted that characteristics of the caregiver network may be associated with unmet needs. Using National Health and Aging Trends Study data, I modeled the association between care configurations and unmet needs for men and women. In generalized linear models, formal care was not associated with unmet need among women or men. Compared with recipients of spousal care, men receiving care from one nonspousal caregiver, and men and women receiving care from any other configuration, had higher odds of unmet needs. The level of difficulty with daily tasks was strongly associated with unmet needs. These findings support monitoring older adults not receiving spousal care, increasing access to formal care, and regularly assessing level of difficulty with daily tasks in clinical and research settings.

Factors Associated With Caregivers' Use of Support Services and Caregivers' Nonuse of Services Sought.

Informal caregivers may face barriers accessing services like respite care, training, and support groups. Using multinomial logistic regression, I modeled caregivers' probability of using all services sought ("all services used") and nonuse of any services sought ("any unused services") as a function of caregiver and care-recipient characteristics. Care-recipient health and function, especially dementia and need for medical task assistance, were associated with all services used and any unused services, and any unused services were more likely among adult children caring for their parents, caregivers of Black and Hispanic older adults, caregivers providing intensive care, caregivers living in metropolitan areas, and residents of states that spend more on increasing access to caregiver services under the National Family Caregiver Support Program. Regularly scheduled caregiving was associated with higher likelihood of all services used, but not with any unused services. Steps should be taken to increase access for caregivers who provide intensive care, care to dementia patients, or assistance with medical tasks and for Hispanic families.

The Relationship Between Rural Health Clinic Use and Potentially Preventable Hospitalizations and Emergency Department Visits Among Medicare Beneficiaries.

PURPOSE: High rates of potentially preventable hospitalizations and emergency department (ED) visits indicate limited primary care access. Rural Health Clinics (RHCs) are intended to increase access to primary care. The goal of this study was to evaluate the role of RHCs and their impact on potentially preventable hospitalizations and ED visits among Medicare beneficiaries based on actual individual-level utilization patterns. METHODS: With Medicare Part A and Part B claims data from 2007 to 2010, we constructed a series of individual-level negative binomial regression models to examine the relationship between RHC use and the number of potentially preventable hospitalizations and ED visits. FINDINGS: RHC use was associated with a 27% increase in potentially preventable hospitalizations and a 24% increase in potentially preventable ED visits among older Medicare enrollees. Among younger, disabled Medicare beneficiaries, RHC use was associated with a 14% increase in potentially preventable hospitalizations and an 18% increase in potentially preventable ED visits. Potentially preventable hospitalizations and ED visits were more common among beneficiaries who were black or who had more chronic conditions. CONCLUSIONS: The results of our study highlight that the Medicare population using RHCs is at especially high risk for potentially preventable hospitalizations and ED visits. The mechanisms behind this are not well understood and should receive continued attention from policy makers and researchers.

Younger Dual-Eligibles Who Use Federally Qualified Health Centers Have More Preventable Emergency Department Visits, but Some Have Fewer Hospitalizations.

OBJECTIVE: To determine whether younger dual-eligibles receiving care at federally qualified health centers (FQHCs) have lower rates of ambulatory care sensitive (ACS) hospitalization and emergency department (ED) visits. DATA SOURCES: We used the 100% Medicare Part A and Part B institutional claims from 2007 to 2010 for dual-eligibles younger than 65 years, enrolled in traditional fee-for-service Medicare, who received care at an FQHC or lived in a primary care service area with an FQHC. METHODS: Our cross-sectional analysis used negative binomial regressions to model ACS hospitalizations and ED visits as a function of prior year FQHC use. The model adjusted for beneficiary age, gender, race, and chronic diseases, as well as county fixed effects, time trends, and race-FQHC use interactions. RESULTS: FQHC use is associated with a decrease in ACS hospitalization rates for whites (2.8 per 1000 persons), but an increase among blacks (2.5 per 1000 persons). FQHC use is also associated with an increase in ACS ED visits, from 27 to 33 more visits per 1000 persons per year, depending on patient race. CONCLUSIONS: ACS hospital use is higher for FQHC users than nonusers, but white FQHC users have fewer ACS hospitalizations. More research is needed to understand how this relationship varies within and between centers.

Use of Federally Qualified Health Centers and Potentially Preventable Hospital Utilization Among Older Medicare-Medicaid Enrollees.

Using Medicare claims data from 2007 to 2010, we sought to determine whether dual eligibles 65 years and older who utilize federally qualified health centers (FQHCs) have lower rates of ambulatory care-sensitive hospitalizations and emergency department visits compared with nonusers. We found that FQHC use is associated with increased ambulatory care-sensitive hospitalization rates for whites and other races, but a decrease among blacks. Depending on race, FQHC use is associated with an increase of 24 to 43 ambulatory care-sensitive emergency department visits per thousand persons annually. More research is needed to understand why FQHC use is associated with these outcomes among dual eligibles.

Iowa Wavering on Medicaid: From Expansion to Modernization.

Iowa is one of six states to expand Medicaid through section 1115 waivers. Iowa's alternative approach to Medicaid expansion, known as the Iowa Health and Wellness Plan, was the result of a bipartisan compromise, motivated by the pending expiration of a preexisting section 1115 waiver that served sixty-five thousand Iowans. The Iowa Health and Wellness Plan emphasizes personal responsibility and private involvement. Key features include beneficiary premiums, incentives for healthy behaviors, and premium assistance for some beneficiaries to purchase insurance in the health insurance marketplace. However, Iowa has struggled to implement its expansion as initially envisioned, due largely to the lack of private insurers willing and able to insure new Medicaid enrollees in the marketplace. In 2016 Iowa will dramatically increase the role of managed care in Medicaid, with the vast majority of beneficiaries receiving almost all Medicaid services through a capitated managed care organization. This article highlights the local factors driving expansion, the interplay of the state and federal political landscape, the challenges of providing consumer choice within Iowa's marketplace, and the future of Iowa's Medicaid program under managed care.

Federally Qualified Health Center Use Among Dual Eligibles: Rates Of Hospitalizations And Emergency Department Visits.

People who are eligible for both Medicare and Medicaid, known as "dual eligibles," disproportionately are members of racial or ethnic minority groups. They face barriers accessing primary care, which in turn increase the risk of potentially preventable hospitalizations and emergency department (ED) visits for ambulatory care-sensitive conditions. Federally qualified health centers provide services known to address barriers to primary care. We analyzed 2008-10 Medicare data for elderly and nonelderly disabled dual eligibles residing in Primary Care Service Areas with nearby federally qualified health centers. Among our findings: There were fewer hospitalizations for ambulatory care-sensitive conditions among blacks and Hispanics who used these health centers than among their counterparts who did not use them (16 percent and 13 percent fewer, respectively). Use of the health centers was also associated with 3 percent and 12 percent fewer hospitalizations for ambulatory care-sensitive conditions among nonelderly disabled blacks and Hispanics, respectively. These findings suggest that federally qualified health centers can reduce disparities in preventable hospitalizations for some dual eligibles. However, further efforts are needed to reduce preventable ED visits among dual eligibles receiving care in the health centers.

Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study.

OBJECTIVES: The objective was to determine the efficacy of coadministration of subcutaneous (SQ) insulin glargine in combination with intravenous (IV) insulin for treating diabetic ketoacidosis (DKA). METHODS: This was a prospective, randomized, controlled trial comparing coadministration of insulin glargine and IV insulin (experimental) with IV insulin (standard care control). The setting was emergency departments (EDs) in two hospitals in Houston, Texas. Patients presenting with blood sugar ≥ 200 mg/dL, pH ≤ 7.3, bicarbonate (HCO3 ) ≤ 18 mg/dL, ketonemia or ketonuria, and anion gap ≥ 16 between November 2012 and April 2013 were enrolled. All patients received IV insulin. Additionally, the experimental group was given SQ insulin glargine within 2 hours of diagnosis. Upon closure of anion gap, patients in the control group were subsequently transitioned to long-acting insulin. In the study group, IV insulin was discontinued and long-acting SQ insulin was reinstituted 24 hours after initial introduction. The primary outcome of time to closure of anion gap (TCAG) was compared between groups using a general linear model (GLM), adjusting for initial anion gap, etiology, and presence of comorbidities. Similarly, the secondary outcome hospital length of stay (LOS) was adjusted for age, etiology, and hospital site in the GLM. Rate of hypoglycemia and intensive care unit (ICU) admission was compared using Fisher's exact test while ICU LOS was compared using Wilcoxon's two-sample test. RESULTS: A total of 40 patients were enrolled in this pilot trial. The estimated mean TCAG was 10.2 hours (SE ± 6.8 hours) in the experimental group and 11.6 hours (SE ± 6.4 hours) in the control group (p = 0.63). The estimated mean hospital LOS was 3.9 days (SE ± 3.4 days) in the experimental group and 4.8 days (SE ± 3.6 days) in the control group (p = 0.66). Incidents of hypoglycemia, rates of ICU admission, and ICU LOS were similar between the groups. CONCLUSIONS: Coadministration of glargine in combination with an insulin infusion in the acute management of DKA is feasible. Further study is needed to determine the true efficacy in terms of TCAG and hospital LOS.

Factors Affecting Staff Perceptions of Tele-ICU Service in Rural Hospitals.

INTRODUCTION: Telemedicine is designed to increase access to specialist care, especially in settings distant from tertiary-care centers. One of the more established telemedicine applications in hospitals is the tele-intensive care unit (tele-ICU). Perceptions of tele-ICU users are not well studied. Thus, we undertook a study focused on assessing staff acceptance at multiple hospitals that had implemented a tele-ICU system. MATERIALS AND METHODS: We designed a survey instrument that gathered perceptions on multiple facets of tele-ICU use and administered it to clinical and administrative staff at 28 hospitals that had implemented a tele-ICU system. We also conducted interviews at half of these hospitals to gain a deeper understanding of factors affecting staff perceptions of tele-ICU services. RESULTS: The 145 survey respondents were generally positive about all facets of the service. Analyses found no significant differences in comparisons between critical access and larger hospitals or between clinical and administrative/managerial respondents, although a few differences between providers and nurses emerged. Respondents at hospitals averaging more tele-ICU use and that had implemented it longer were significantly (p<0.05) more positive in their responses on multiple survey items than other respondents. Interviews corroborated and provided insight into survey responses. CONCLUSIONS: Tele-ICU was particularly valued when critical access hospitals retained critical care patients during special circumstances and when the tele-ICU hub could monitor patients to provide relief for local providers and nurses. Tele-ICU can aid rural hospitals, but multiple delivery models are warranted to meet disparate needs.

Effect of tele-emergency services on recruitment and retention of US rural physicians.

INTRODUCTION: As competition for physicians intensifies in the USA, rural areas are at a disadvantage due to challenges unique to rural medical practice. Telemedicine improves access to care not otherwise available in rural settings. Previous studies have found that telemedicine also has positive effects on the work environment, suggesting that telemedicine may improve rural physician recruitment and retention, although few have specifically examined this. METHODS: Using a mixed-method approach, clients of a single telemedicine service in the Upper Midwestern USA were surveyed and interviewed about their views of the impact of tele-emergency on physician recruitment and retention and the work environment. Surveys were completed by 292 clinical and administrative staff at 71 hospitals and semi-structured interviews were conducted with clinicians and administrators at 16 hospitals. RESULTS: Survey respondents agreed that tele-emergency had a positive effect on physician recruitment and retention and related workplace factors. Interviewees elucidated how the presence of tele-emergency played an important role in enhancing physician confidence, providing educational opportunities, easing burden, and supplementing care, workplace factors that interviewees believed would impact recruitment and retention. However, gains were limited by hospitals' interpretation of the Emergency Medical Treatment and Labor Act as requiring on-site physician coverage even if tele-emergency was used. CONCLUSIONS: Results indicate that, all other factors being equal, tele-emergency increases the likelihood of physicians entering and remaining in rural practice. New regulatory guidance by the Centers for Medicare and Medicaid Services related to on-site physician coverage will likely accelerate implementation of tele-emergency services in rural hospitals. Telemedicine may prove to be an increasingly valuable recruitment and retention tool for rural hospitals as competition for physicians intensifies.

Lessons from tele-emergency: improving care quality and health outcomes by expanding support for rural care systems.

Tele-emergency services provide immediate and synchronous audio/video connections, most commonly between rural low-volume hospitals and an urban "hub" emergency department. We performed a systematic literature review to identify tele-emergency models and outcomes. We then studied a large tele-emergency service in the upper Midwest. We sent a user survey to all seventy-one hospitals that used the service and received 292 replies. We also conducted telephone interviews and site visits with ninety clinicians and administrators at twenty-nine of these hospitals. Participants reported that tele-emergency improves clinical quality, expands the care team, increases resources during critical events, shortens time to care, improves care coordination, promotes patient-centered care, improves the recruitment of family physicians, and stabilizes the rural hospital patient base. However, inconsistent reimbursement policy, cross-state licensing barriers, and other regulations hinder tele-emergency implementation. New value-based payment systems have the potential to reduce these barriers and accelerate tele-emergency expansion.

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.

The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.

Structure-based drug design targeting an inactive RNA conformation: exploiting the flexibility of HIV-1 TAR RNA.

The targeting of RNA for the design of novel anti-viral compounds represents an area of vast potential. We have used NMR and computational methods to model the interaction of a series of synthetic inhibitors of the in vitro RNA binding activities of a peptide derived from the transcriptional activator protein, Tat, from human immunodeficiency virus type 1. Inhibition has been measured through the monitering of fluorescence resonance energy transfer between fluorescently labeled peptide and RNA components. A series of compounds containing a bi-aryl heterocycle as one of the three substituents on a benzylic scaffold, induce a novel, inactive TAR conformation by stacking between base-pairs at the site of a three-base bulge within TAR. The development of this series resulted in an enhancement in potency (with Ki < 100 nM in an in vitro assay) and the removal of problematic guanidinium moieties. Ligands from this series can act as inhibitors of Tat-induced transcription in a cell-free system. This study validates the drug design strategy of using a ligand to target the RNA receptor in a non-functional conformation.