Comparative α-Helicity of Cyclic Pentapeptides in Water

Helix-constrained polypeptides have attracted great interest for modulating protein-protein interactions (PPI). It is not known which are the most effective helix-inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X-1-X-5) were compared here, using circular dichroism and 2D NMR spectroscopy, for a-helix induction in simple model pentapeptides, Ac-cyclo(1,5)-[X-1-Ala-Ala-Ala-X-5]-NH2, in water. In this very stringent test of helix induction, a Lys1 -> Asp5 lactam linker conferred greatest alpha-helicity, hydrocarbon and triazole linkers induced a mix of alpha- and 3(10)-helicity, while thio-and dithioether linkers produced less helicity. The lactam-linked cyclic pentapeptide was also the most effective a-helix nucleator attached to a 13-residue model peptide

Correction:Structural and Functional Insights into an Archaeal Lipid Synthase

(Cell Reports 33, 108294-1–9.e1–e4; October 20, 2020) In the originally published version of this article, the supplemental information file containing Figures S1–S7 and Table S1 was inadvertently removed. The complete supplemental information file is now included with the paper online. The production team regrets this error

Structural and Functional Insights into an Archaeal Lipid Synthase

The UbiA superfamily of intramembrane prenyltransferases catalyzes an isoprenyl transfer reaction in the biosynthesis of lipophilic compounds involved in cellular physiological processes. Digeranylgeranylglyceryl phosphate (DGGGP) synthase (DGGGPase) generates unique membrane core lipids for the formation of the ether bond between the glycerol moiety and the alkyl chains in archaea and has been confirmed to be a member of the UbiA superfamily. Here, the crystal structure is reported to exhibit nine transmembrane helices along with a large lateral opening covered by a cytosolic cap domain and a unique substrate-binding central cavity. Notably, the lipid-bound states of this enzyme demonstrate that the putative substrate-binding pocket is occupied by the lipidic molecules used for crystallization, indicating the binding mode of hydrophobic substrates. Collectively, these structural and functional studies provide not only an understanding of lipid biosynthesis by substrate-specific lipid-modifying enzymes but also insights into the mechanisms of lipid membrane remodeling and adaptation

Helical cyclic pentapeptides constrain HIV-1 Rev peptide for enhanced RNA binding

HIV-1 Rev is a 116 residue transporter protein that enters the host cell nucleus and uses its 17 amino acid segment (Rev34–50) to bind and capture a specific piece of RNA, the Rev Response Element (RRE), for transport to the cytoplasm. This is critical for HIV replication. In isolation, Rev34–50 shows negligible structure in water, but is alpha helical in a mixture of water and 2,2,2-trifluoroethanol (TFE) or when bound to RRE. Here we report that helix-constrained cyclic pentapeptides, either appended to the N-terminus or incorporated within Rev34–50, are efficient helix nucleators in water. They induce up to 90% alpha helicity for isolated Rev peptides in water and confer high RNA-binding affinity

Gestational diabetes mellitus and retinal microvasculature.

BACKGROUND: Small-vessel dysfunction may be an important consequence of chronic hyperglycemia. We examined the association between gestational diabetes mellitus (GDM), a state of transient hyperglycemia during pregnancy, and retinal microvascular changes in pregnant women at 26-28 weeks of pregnancy. METHODS: A total of 1136 pregnant women with singleton pregnancies were recruited during their first trimester at two major Singapore maternity hospitals in an on-going birth cohort study. Participants underwent an oral glucose tolerance test and retinal imaging at 26-28 weeks gestation (n = 542). We used the 1999 World Health Organization (WHO) criteria to define GDM: ≥7.0 mmol/L for fasting glucose and/or ≥7.8 mmol/L for 2-h post-glucose. Retinal microvasculature was measured using computer software (Singapore I Vessel Analyzer, SIVA version 3.0, Singapore Eye Research Institute, Singapore) from the retinal photographs. RESULTS: In a multiple linear regression model adjusting for age, ethnicity and maternal education, mothers with GDM had narrower arteriolar caliber (-1.6 μm; 95% Confidence Interval [CI]: -3.1 μm, -0.2 μm), reduced arteriolar fractal dimension (-0.01 Df; 95% CI: -0.02 Df, -0.001 Df;), and larger arteriolar branching angle (1.8°; 95% CI: 0.3°, 3.3°) than mothers without GDM. After further adjusting for traditional risks of GDM, arteriolar branching angle remained significantly larger in mothers with GDM than those without GDM (2.0°; 95% CI: 0.5°, 3.6°). CONCLUSIONS: GDM was associated with a series of retinal arteriolar abnormalities, including narrower caliber, reduced fractal dimension and larger branching angle, suggesting that transient hyperglycemia during pregnancy may cause small-vessel dysfunction

Clinical Use of Mood Stabilizers With Antidepressants in Asia Report From the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) Projects in 2004 and 2013

Abstract Objective: As most reports concerning treatment with combinations of mood stabilizer (MS) with antidepressant (AD) drugs are based in the West, we surveyed characteristics of such cotreatment in 42 sites caring for the mentally ill in 10 Asian countries. Methods: This cross-sectional, pharmacoepidemiologic study used 2004 and 2013 data from the REAP-AD (Research Study on Asian Psychotropic Prescription Patterns for Antidepressants) to evaluate the rates and doses of MSs given with ADs and associated factors in 4164 psychiatric patients, using standard bivariate methods followed by multivariable logistic regression modeling. Results: Use of MS + AD increased by 104% (5.5% to 11.2%) between 2004 and 2013 and was much more associated with diagnosis of bipolar disorder than major depression or anxiety disorder, as well as with hospitalization > outpatient care, psychiatric > general-medical programs, and young age (all P < 0.001), but not with country, sex, or AD dose. Conclusions: The findings provide a broad picture of contemporary use of MSs with ADs in Asia, support predictions that such treatment increased in recent years, and was associated with diagnosis of bipolar disorder, treatment in inpatient and psychiatric settings, and younger age

A comparison of clinical characteristics of older adults treated with antidepressants in general and psychiatric hospitals in Asia

Abstract Aim: This study compared the demographics, clinical characteristics, and antidepressant prescription patterns between Asian patients aged 50 years and older attending psychiatric hospitals and those attending general hospitals. Methods: In total, 955 patients (604 in general hospitals, 351 in psychiatric hospitals) aged 50 years or older treated with antidepressants in 10 Asian countries and territories were examined. Patients' demographics, clinical features, and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. Results: Binary logistic regression revealed that high income and diagnosis of schizophrenia were independently associated with psychiatric hospital treatment, whereas outpatient care, diagnosis of anxiety disorders, and multiple major medical conditions were independently associated with general hospital treatment. In addition, tetracyclic and noradrenergic and specific serotonergic antidepressants were more likely to be prescribed in general hospitals. Conclusion: Older adults treated with antidepressants showed different demographic and clinical features between general hospitals and psychiatric hospitals in Asia

New developments in flavivirus drug discovery

Introduction: Flaviviruses are major causes of infectious disease. The vast global, social and economic impact due to morbidity and mortality associated with diseases caused by these viruses urgently demands effective therapeutic interventions. There is currently no specific antiviral therapy available for the effective clinical treatment of infections by any of the flaviviridae. Development of more effective vaccines and antiviral agents for the prevention and treatment of most flavivirus infections remains a clear public health priority in the 21st century.Areas covered: This review describes some of the recent discoveries in the field of flavivirus inhibitor development, with a particular focus on targeting viral proteins. Emphasis is placed on the advances published during the 2012-2015 period.Expert opinion: The field of drug discovery targeting viral proteins has progressed slowly in recent years. New information, particularly on structures, location and mechanisms of action of established protein targets have been reported. There have also been studies on repurposing known drugs as templates for targeting flavivirus proteins and these hits could be promising templates for developing new more potent inhibitors. Further research should be conducted to improve in vitro assays that better reflect the conditions found in cellular environments