Synthesis and structure activity relationships of ring D modified steroidal hormones

Includes bibliographical references.The synthesis of steroidal 14α,16-methano, 14α,17-methano-, 14α,17-ethano- and 14α,17-propano estradiol analogues as well as 14α-alkyl and 14α-functionalised-alkyl estradiol analogues was investigated. Furthermore, the synthesis of 17β-hydroxy-17α, 14-(epoxymethano)androst-4-en-3-one was undertaken and acid-mediated rearrangement of the 14,17-etheno bridged testosterone analogue gave the 14,16-ethano analogue of androst-4-en-3,17-dione. Established ring D cycloaddition and oxidative cleavage methodology gave ring D 14α-formyl and 14α, 17α-diformyl compounds as key intermediates in the overall synthetic plan. Chemoselective- and stereoselective nucleophilic addition at C-14¹ of the 14α-formyl-3-methoxyestra-1,3,5(10)-trien-17-one provided access to 14α-alkyl- and 14α-alkyl-functionalised 19-norsteroids for elaboration toward 14α,17-propano- and 14α-alkylamide estradiol analogues. Synthesis of the 14α,17-methano bridged steroid was attainable indirectly through intramolecular pinacol coupling between the 17-oxo- and 14-formyl group of 14αformyl- 3-methoxyestra-1,3,5(10)-trien-17-one. The 14α, 16-methano bridged steroid was synthesised via base-mediated intramolecular cyclisation of 14-(toluene-p-sulfonyloxy)methyl-3-methoxyestra-1,3,5( 1 0)-trien-17-one. Novel compounds were characterised with the aid of high field NMR techniques. A X-ray crystal structure determination of the strained ring D 14α, 17-methano bridged estriol analogue corroborated its structure. The minimum energy conformation of novel estradiol analogues were superimposed on estradiol, and their least square fit values determined and discussed in relation to biological activity. These analogues will contribute toward defining the structural parameters responsible for certain pattern of hormonal activity, and hence, the ultimate goal of predictive drug design

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease