In vitro and in vivo characterization of potent antileishmanial methionine aminopeptidase 1 inhibitors

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL, and current drug regimens present several drawbacks, such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase 1 of L. major (MetAP1Lm), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activities of eight novel MetAP1 inhibitors (OJT001 to OJT008) were investigated. Three compounds, OJT006, OJT007, and OJT008, demonstrated potent antiproliferative effects in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect in transgenic L. major promastigotes overexpressing MetAP1Lm was diminished by almost 10-fold in comparison to the effect in wild-type promastigotes. Furthermore, the in vivo activities of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the footpad parasite load in the control group, OJT008 decreased the footpad parasite load significantly, by 86%, and exhibited no toxicity in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection

HIV-TB Coinfection among 57 Million Pregnant Women, Obstetric Complications, Alcohol Use, Drug Abuse, and Depression

Objective. HIV and tuberculosis represent diseases of major public health importance worldwide. Very little is known about HIV-TB coinfection among pregnant women, especially from industrialized settings. In this study, we examined the association between TB, HIV, and HIV-TB coinfection among pregnant mothers and obstetric complications, alcohol use, drug abuse, and depression. Method. We examined inpatient hospital discharges in the United States from January 1, 2002, through December 31, 2014. We employed multivariable survey logistic regression to generate adjusted estimates for the association between infection status and study outcomes. Results. We analyzed approximately 57 million records of pregnant women and their delivery information. HIV-TB coinfection was associated with the highest risks for several obstetric complications, alcohol use, and drug abuse. The risk for alcohol abuse was more than twice as high among HIV-monoinfected as compared to TB-monoinfected mothers. That risk gap more than doubled with HIV-TB coinfection. Both HIV-monoinfected and HIV-TB coinfected mothers experienced similarly increased risks for depression. Conclusions. Mothers with HIV-TB coinfection experienced relatively heightened risks for obstetric complications, alcohol use, and drug abuse. The findings of this study underscore the importance of augmenting and enhancing social and structural support systems for HIV-TB coinfected pregnant women

Discovery of Clioquinol and analogues as novel inhibitors of Severe Acute Respiratory Syndrome Coronavirus 2 infection, ACE2 and ACE2 - Spike protein interaction in vitro

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for coronavirus disease 2019 (COVID-19), has resulted in an ongoing pandemic. Presently, there are no clinically approved drugs for COVID-19. Hence, there is an urgent need to accelerate the development of effective antivirals. Herein, we discovered Clioquinol (5-chloro-7-iodo-8-quinolinol (CLQ)), a Food and Drug Administration (FDA) approved drug, and two of its analogues (7-bromo-5-chloro-8-hydroxyquinoline (CLBQ14); and 5, 7-Dichloro-8-hydroxyquinoline (CLCQ)) as potent inhibitors of SARS-CoV-2 infection-induced cytopathic effect in vitro. In addition, all three compounds showed potent anti-exopeptidase activity against recombinant human angiotensin-converting enzyme 2 (rhACE2) and inhibited the binding of rhACE2 with SARS-CoV-2 Spike (RBD) protein. CLQ displayed the highest potency in the low micromolar range, with its antiviral activity showing a strong correlation with inhibition of rhACE2 and rhACE2-RBD interaction. Altogether, our findings provide a new mode of action and molecular target for CLQ and validates this pharmacophore as a promising lead series for the clinical development of potential therapeutics for COVID-19

Validation of Methionine Aminopeptidase-1 as a Potential Chemotherapeutic Target for Leishmania major

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Garamond} span.s1 {font: 12.0px \u27Times New Roman\u27} span.s2 {font: 7.0px Garamond} Cutaneous leishmaniasis is a vector-borne disease caused by Leishmania major affecting millions of people throughout the world. It is an emerging concern in the United States due to military establishments in endemic countries. Treatment for the disease is highly toxic and the lack of vaccines emphasizes on the need for alternative drug treatments. Aminopeptidase inhibitors have shown promising results against malaria and tuberculosis. Methionine aminopeptadse-1 (MetAP1) catalyzes the removal of the N-terminal methionine residue from peptides and proteins. The human MetAP1 has low similarity with the Leishmania enzyme making it a potential chemotherapeutic target. The MetAP1 gene was amplified through PCR from L. major genomic DNA and cloned into the expression vector pRSET A. The expression and purification of the recombinant enzyme was performed and the biochemical characterization of the enzyme is underway. Transgenic promastigotes of L. major (Friedlin clone V1) expressing firefly luciferase were used to determine the antiparasitic activity of putative MetAP1 inhibitors. Eight compounds were tested and three of them showed great anti-leishmanial activity at 0.78μM for 72 hr. with 5-6% survival (IC50 = 125 nM). The enzymatic assay using the recombinant enzyme will be developed to determine the inhibitors’ specificity

Pre-clinical pharmacokinetics, tissue distribution and physicochemical studies of CLBQ14, a novel methionine aminopeptidase inhibitor for the treatment of infectious diseases

Introduction: CLBQ14, a derivative of 8-hydroxyquinoline, exerts its chemotherapeutic effect by inhibiting methionine aminopeptidase (MetAP), the enzyme responsible for the post-translational modification of several proteins and polypeptides. MetAP is a novel target for infectious diseases. CLBQ14 is selective and highly potent against replicating and latent Mycobacterium tuberculosis making it an appealing lead for further development. Methods: The physicochemical properties (solubility, pH stability and lipophilicity), in vitro plasma stability and metabolism, pre-clinical pharmacokinetics, plasma protein binding and tissue distribution of CLBQ14 in adult male Sprague-Dawley rats were characterized. Results: At room temperature, CLBQ14 is practically insoluble in water (80 mg/mL); it has a log P value of 3.03 ± 0.04. CLBQ14 exhibits an inverse Z-shaped pH decomposition profile; it is stable at acidic pH but is degraded at a faster rate at basic pH. It is highly bound to plasma proteins (\u3e91%), does not partition to red blood cells (B/P ratio: 0.83 ± 0.03), and is stable in mouse, rat, monkey and human plasma. CLBQ14 exhibited a bi-exponential pharmacokinetics after intravenous administration in rats, bioavailability of 39.4 and 90.0%, respectively from oral and subcutaneous route. We observed a good correlation between predicted and observed rat clearance, 1.90 ± 0.17 L/kg/h and 1.67 ± 0.08 L/kg/h, respectively. Human hepatic clearance predicted from microsomal stability data and from the single species scaling were 0.80 L/hr/kg and 0.69 L/h/kg, respectively. CLBQ14 is extensively distributed in rats; following a 5 mg/kg intravenous administration, lowest and highest concentrations of 15.6 ± 4.20 ng/g of heart and 405.9 ± 77.11 ng/g of kidneys, respectively, were observed. In vitro CYP reaction phenotyping demonstrates that CLBQ14 is metabolized primarily by CYP 1A2. Conclusion: CLBQ14 possess appealing qualities of a drug candidate. The studies reported herein are imperative to the development of CLBQ14 as a new chemical entity for infectious diseases

HIV-TB Coinfection among 57 Million Pregnant Women, Obstetric Complications, Alcohol Use, Drug Abuse, and Depression

Objective. HIV and tuberculosis represent diseases of major public health importance worldwide. Very little is known about HIV-TB coinfection among pregnant women, especially from industrialized settings. In this study, we examined the association between TB, HIV, and HIV-TB coinfection among pregnant mothers and obstetric complications, alcohol use, drug abuse, and depression. Method. We examined inpatient hospital discharges in the United States from January 1, 2002, through December 31, 2014. We employed multivariable survey logistic regression to generate adjusted estimates for the association between infection status and study outcomes. Results. We analyzed approximately 57 million records of pregnant women and their delivery information. HIV-TB coinfection was associated with the highest risks for several obstetric complications, alcohol use, and drug abuse. The risk for alcohol abuse was more than twice as high among HIV-monoinfected as compared to TB-monoinfected mothers. That risk gap more than doubled with HIV-TB coinfection. Both HIV-monoinfected and HIV-TB coinfected mothers experienced similarly increased risks for depression. Conclusions. Mothers with HIV-TB coinfection experienced relatively heightened risks for obstetric complications, alcohol use, and drug abuse. The findings of this study underscore the importance of augmenting and enhancing social and structural support systems for HIV-TB coinfected pregnant women

Role of Social Determinants of Health in Widening Maternal and Child Health Disparities in the Era of Covid-19 Pandemic

We present a conceptual model that describes the social determinants of health (SDOH) pathways contributing to worse outcomes in minority maternal and child health (MCH) populations due to the current COVID-19 pandemic. We used International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10) codes in the categories Z55-Z65 to identify SDOH that potentially modulate MCH disparities. These SDOH pathways, coupled with pre-existing comorbidities, exert higher-than-expected burden of maternal-fetal morbidity and mortality in minority communities. There is an urgent need for an increased infusion of resources to mitigate the effects of these SDOH and avert permanent truncation in quality and quantity of life among minorities following the COVID-19 pandemic. Key words: • COVID-19 • Maternal and child health disparity • Social determinants of health • Minority women   Copyright © 2020 Dongarwar et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited

Temporal trends of gestational malaria in the United States

Background: Although regarded as rare in the United States (US), increased global traffic and importation of malaria from endemic countries may lead to a rise in gestational malaria in the US. Methods: This multi-year retrospective study analyzed trends in diagnosed cases of gestational malaria from 2002 to 2017 using joinpoint regression models. We also assessed the association between gestational malaria and selected maternal-fetal adverse outcomes. Results: Mothers diagnosed with gestational malaria tended to be older, and the majority of diagnosed cases (52.9%) were among Non-Hispanic (NH) Blacks. Diagnosed cases of gestational malaria are on the rise in the US. Mothers diagnosed with gestational malaria were 5 times as likely (OR = 5.05, 95% CI: 4.05–6.29) to be anemic as compared to those without malaria. Compared to NH-Whites, NH-Black mothers were twice as likely to experience stillbirth, had nearly 50% greater adjusted odds of severe preeclampsia, and had about 30% elevated likelihood for preterm labor. Conclusions: There is a need to dedicate appropriate resources to identify women that are at risk for gestational malaria in order to prevent related pregnancy complications

Success of Maternal and Child Health Pipeline Training Programs: Alumni Survey Results

IntroductionThe Maternal and Child Health (MCH) Pipeline Training Program, promotes development of a diverse health workforce by training undergraduate students from underrepresented minorities. We aimed to evaluate the success of this program based on three domains: (1) demographic characteristics, (2) academic and career development, and (3) attitudes towards the field of MCH and the training programs among graduates.MethodsThree domains of success were determined through a collaborative effort between current program directors and the funding agency project officers. The survey with questions related to the three domains was distributed via an online platform to graduates from seven sites (one former site and six current sites). Data were analyzed and presented utilizing descriptive statistics.ResultsThe survey was distributed to 550 graduates, 162 responded (37% response rate). Demographically, 78% were female, 54% were Black/African American, 22% were Latinx and 83% did not report any disability. Eighty percent of respondents applied to graduate/professional schools, 67% received admission. Graduates often continued to work in MCH fields (70%). Majority felt confident and knowledgeable in the field (89%) and agreed the faculty were supportive at their training sites (90%).ConclusionThe study highlights successes in recruiting from underrepresented minorities, particularly Black/African Americans and first-time college goers in the family into the MCH Pipeline Training Programs. Programs were successful in furthering academic and career development for most trainees. Attitudes towards MCH and the training programs were overwhelmingly positive. Continued support of these programs is critical in addressing health disparities and achieving health equity

Tuberculosis during pregnancy in the United States: Racial/ethnic disparities in pregnancy complications and in-hospital death.

Despite decades of efforts to eliminate tuberculosis (TB) in the United States (US), TB still contributes to adverse ill health, especially among racial/ethnic minorities. According to the Centers for Disease Control and Prevention, in 2016, about 87% of the TB cases reported in the US were among racial and ethnic minorities. The objective of this study is to explore the risks for pregnancy complications and in-hospital death among mothers diagnosed with TB across racial/ethnic groups in the US.This retrospective cohort study utilized National Inpatient Sample data for all inpatient hospital discharges in the US. We analyzed pregnancy-related hospitalizations and births in the US from January 1, 2002 through December 31, 2014 (n = 57,393,459). Multivariable logistic regression was applied to generate odds ratios for the association between TB status and the primary study outcomes (i.e., pregnancy complications and in-hospital death) across racial/ethnic categories.The prevalence of TB was 7.1 per 100,000 pregnancy-related hospitalizations. The overall prevalence of pregnancy complications was 80% greater among TB-infected mothers than their uninfected counterparts. Severe pre-eclampsia, eclampsia, placenta previa, post-partum hemorrhage, sepsis and anemia occurred with greater frequency among mothers with a TB diagnosis than those without TB, irrespective of race/ethnicity. The rate of in-hospital death among TB patients was 37 times greater among TB-infected than in non-TB infected mothers (468.8 per 100,000 versus 12.6 per 100,000). A 3-fold increased risk of in-hospital death was observed among black TB-negative mothers compared to their white counterparts. No racial/ethnic disparities in maternal morbidity or in-hospital death were found among mothers with TB disease.TB continues to be an important cause of morbidity and mortality among pregnant women in the US. Resources to address TB disease should also target pregnant women, especially racial/ethnic minorities who bear the greatest burden of the disease