New Neplanocin Analogues. V. A Potent Adenosylhomocysteine Hydrolase Inhibitor Lacking Antiviral Activity. Synthesis And Antiviral Activity Of 6″-Carboxylic Acid Derivatives Of Neplanocin A 1

Abstract

The 6′-carboxylic acid derivative of neplanocin A 3 was synthesized from NPA, and was converted to the corresponding methyl ester 4 and amides 5 and 6. These were evaluated for their anti-RNA-virus activities. Of the derivatives synthesized, only 5 was active against RNA viruses within the concentration range of 0.14-4.88 μg/mL. Compounds 3 and 5 showed a potent inhibitory effect on S-adenosylhomocysteine (AdoHcy) hydrolase from rabbit erythrocytes. Although a close correlation between the inhibitory effect of adenosine analogues on AdoHcy hydrolase and their antiviral potency has been demonstrated, 3 did not show any anti-RNA-virus activities.

     

Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis

Introduction

The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE^-/-Fas^-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.

Methods

Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.

Results

In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (P_{L, LP} < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (P_L < 0.05) and oxidized phospholipids (oxPLs) (P_{L, LP} < 0.005), and elevated total and vertebral bone mineral density (P_{L, LP} < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68⁺ macrophages (P_LP < 0.01), significantly increased mean α-actin stained area (P_LP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (P_{L, LP} < 0.0005) and VCAM-1 (P_L < 0.0002).

Conclusions

L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.     

Molecular architecture of the ribosome‐bound Hepatitis C Virus internal ribosomal entry site RNA

Internal ribosomal entry sites (IRESs) are structured cis‐acting RNAs that drive an alternative, cap‐independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo‐EM reconstructions of the ribosome 80S‐ and 40S‐bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P‐site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA‐driven translation initiation.     

Cryptically dimorphic caste differences in a Neotropical, swarm-founding paper wasp genus, Parachartergus (Hymenoptera: Vespidae)

Morphological differences in body shape between females of different reproductive conditions (in terms of insemination and ovarian development) were examined in two species of the Neotropical polistine genus Parachartergus: P. smithii and P. fraternus. The present study shows, for the first time, that non‐size‐based morphological divergence between queens and workers occurs in Parachartergus, an epiponine genus once believed to have little or no morphological caste differences. In the P. smithii colony examined, queens were significantly larger than workers in five of the eight body parts measured (head width, eye width, genal width, mesosomal length, wing length, first metasomal tergum width, and width and length of the second tergum), but the mean values of wing length and first and second tergum widths were not significantly different between them. The queen : worker size ratios tended to be greater anteriorly and smaller posteriorly, although the size ratio was greatest in second tergum length. Analysis of covariance (ancova ) with mesosomal length as covariate showed that queens had proportionally wider heads and narrower first terga than did workers. In the P. fraternus colony, size differences between queens and workers were not significant, and there was little or no difference in shape, but queens had significantly proportionally wider first terga than did workers.     

Locking out predators by silk,a new counterattack behaviour in a social spider mite

1. A type of arms race that includes predation, counterattacks and cross‐counterattacks occurs between the phytophagous mite Stigmaeopsis nanjingensis (Ma et Yuan), which lives in self‐woven nests and exhibits cooperative sociality, and its specialised phytoseiid mite predator, Typhlodromus bambusae Ehara. 2. First, the efficiency of the S. nanjingensis (prey) counterattacking T. bambusae (predator) was observed. The prey females frequently locked the immature predators out of their nests using silk web, and the predators subsequently died of starvation. Furthermore, the prey males often killed immature T. bambusae mites after they invaded the nests. 3. This reversal of roles in the predator–prey system was then re‐reversed (returned to a normal state) by the behaviour of T. bambusae females. Immature predators could maintain their predacious natures due to the presence of attending adult females, which are able to cope with the prey counterattack behaviours.