Nucleic acid recognition and antiviral activity of 1,4-substituted terphenyl compounds mimicking all faces of the HIV-1 Rev protein positively-charged α-helix

Small synthetic molecules mimicking the three-dimensional structure of α-helices may find applications as inhibitors of therapeutically relevant protein-protein and protein-nucleic acid interactions. However, the design and use of multi-facial helix mimetics remains in its infancy. Here we describe the synthesis and application of novel bilaterally substituted p-terphenyl compounds containing positively-charged aminoalkyl groups in relative 1,4 positions across the aromatic scaffold. These compounds were specifically designed to mimic all faces of the arginine-rich α-helix of the HIV-1 protein Rev, which forms deeply embedded RNA complexes and plays key roles in the virus replication cycle. Two of these molecules recognized the Rev site in the viral RNA and inhibited the formation of the RRE-Rev ribonucleoprotein complex, a currently unexploited target in HIV chemotherapy. Cellular assays revealed that the most active compounds blocked HIV-1 replication with little toxicity, and likely exerted this effect through a multi-target mechanism involving inhibition of viral LTR promoter-dependent transcription and Rev function. Further development of this scaffold may open new avenues for targeting nucleic acids and may complement current HIV therapies, none of which involve inhibitors interfering with the gene regulation processes of the virus.This project was supported by Ministerio de Economía y Competitividad of Spain (Grants BFU2012–30770 and BFU2015–65103-R to J.G.; CTQ2013-43310 and CTQ2017-84249-P to S.F. and FIS PI16CIII/0034 to J.A.; and FPU15/01485 predoctoral fellowship to D.M.S.), Generalitat Valenciana of Spain (FPA/2015/014 and APOTIP/2016/A007 to J.G. and PROMETEOII/2014/073 to S.F.), the Spanish AIDS Research Network (RD16CIII/0002/0001-ISCIII–FEDER to J.A.), Universidad Católica de Valencia (2017-114-001 and 2018-114-001 to J.G.), and European AIDS Vaccine Initiative 2020 (ID 681137 to J.A.). The authors thank Ainhoa Sánchez for carrying out initial fluorescence anisotropy experiments, Ángel Cantero-Camacho for designing and testing the primers used to amplify LTRc, and Jerónimo Bravo and Antonio Pineda for facilitating access to ITC equipment. Plasmid pLTR(HTLV)-luc (pGL4.20-U3R) was kindly donated by Thomas Kress.S

Mechanisms of vascular damage in systemic sclerosis

Although being classified as autoimmune connective tissue disease, dominant components of the pathophysiology of systemic sclerosis (SSc) consists of mechanisms of vascular damage, which can occur early in the course of the disease. Amongst them are abnormal vasoreactivity, hypoxia, insufficient neoangiogenesis and direct damage of vascular and perivascular cells. They result in a decreased capillary blood flow, and subsequently in clinically overt symptoms such as Raynaud's syndrome and fingertip ulcers. In addition, in active disease vascular pathology can affect various other organs, predominantly the lung, the kidney, the heart but also the gastrointestinal tract. Vascular pathology contributes also significantly to overall morbidity and mortality in SSc patients and reduces life expectancy by at least a decade. Fortunately, molecular biology has revealed a number of underlying pathways on the cellular and subcellular levels, including key factors of the aberrant function of (peri)vascular cells and autoimmune effector cells, the dysregulation of vasoconstrictive molecules and their receptors, the upregulation of intracellular signaling kinases and the altered balance of hypoxia-induced vascular growth factors. This increasing knowledge of vascular pathology in SSc has also resulted in novel therapeutic approaches ranging from endothelin antagonists to application of progenitor cells to counteract this aberrant vascular pathology and to support the repair of the dysfunctional vasculature