HIV-1 is able to replicate in primary human macrophages without stimulating innate immunity despite reverse transcription of genomic RNA into double stranded DNA, an activity that might be expected to trigger innate pattern recognition receptors (PRRs). We hypothesized that, if correctly orchestrated HIV-1 uncoating and nuclear entry is important for evasion of innate sensors, then manipulation of specific interactions between HIV-1 capsid (CA) and host factors that putatively regulate these processes should trigger PRRs and stimulate type 1 interferon secretion. Here we show that HIV-1 CA mutants N74D and P90A, which are impaired for interaction with cofactors Cleavage and Polyadenylation Specificity Factor subunit 6 (CPSF6) and cyclophilins (Nup358 and CypA) respectively(1-2), cannot replicate in primary human monocyte derived macrophages (MDM) because they trigger innate sensors leading to nuclear translocation of NFκB and IRF3, the production of soluble type-1 interferon (IFN) and induction of an antiviral state. Depletion of CPSF6 with shRNA expression allows wild type virus to trigger innate sensors and interferon production. In each case, suppressed replication is rescued by IFN-receptor blockade demonstrating a role for IFN in restriction. IFN production is dependent on viral reverse transcription but not integration suggesting that a viral reverse transcription product comprises the HIV-1 pathogen associated molecular pattern (PAMP). Finally, we show that we can pharmacologically induce wild type HIV-1 infection to stimulate IFN secretion and an antiviral state using a non-immunosuppressive cyclosporine analogue. We conclude that HIV-1 has evolved to utilize CPSF6 and cyclophilins to cloak its replication allowing evasion of innate immune sensors and induction of a cell autonomous innate immune response in primary human macrophages (Extended Data Fig 1).
There was an error published in J. Cell Sci. 120, 929-942. We apologise for the incorrect publication of a reference, for which the wrong year, title and journal details were given. The correct reference is shown below.
We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1−ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.
Using small, flat aromatic rings as components of fragments or molecules is a common practice in fragment-based drug discovery and lead optimization. With an increasing focus on the exploration of novel biological and chemical space, and their improved synthetic accessibility, 3D fragments are attracting increasing interest. This study presents a detailed analysis of 3D and 2D ring fragments in marketed drugs. Several measures of properties were used, such as the type of ring assemblies and molecular shapes. The study also took into account the relationship between protein classes targeted by each ring fragment, providing target-specific information. The analysis shows the high structural and shape diversity of 3D ring systems and their importance in bioactive compounds. Major differences in 2D and 3D fragments are apparent in ligands that bind to the major drug targets such as GPCRs, ion channels, and enzymes.
The structure-activity relationships of a series of novel antifilarial antimycin A1 analogues have been investigated by using computational chemistry and multivariate statistical techniques. The physiochemical descriptors calculated in this way contained information which was useful in the classification of compounds according to their in vitro antifilarial activity. This approach generated a 53 parameter descriptor set, which was reduced with a multivariate pattern recognition package, ARTHUR. Regression analysis of the reduced set yielded several statistically significant regression equations; e.g.-log in vitro activity = 0.017 mp + 0.65 log P - 0.81ESDL10-7.33 (R = 0.9). With use of this equation, it was possible to make predictions for further untested analogues. The analysis indicated that membrane or lipid solubility is an important determinant in biological activity agreeing with the proposed primary mode of action of the compounds as disrupters of cuticular glucose uptake.
Mitochondrial permeability transition, as the consequence of opening of a mitochondrial permeability transition pore (mPTP), is a cellular catastrophe. Initiating bioenergetic collapse and cell death, it has been implicated in the pathophysiology of major human diseases, including neuromuscular diseases of childhood, ischaemia-reperfusion injury and age related neurodegenerative disease. mPTP represents a major therapeutic target, as opening can be prevented by a number of compounds. However, clinical studies have so far been disappointing. We therefore address the prospects and challenges faced in translating in vitro findings to clinical benefit. We review the role of mPTP opening in disease, discuss recent findings defining the putative structure of mPTP and explore strategies to identify
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