The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability... Show moreThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry. A systematic structure-activity relationship (SAR) study demonstrated that a 3- or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity. Show less
Scherpenzeel, M. van; Timal, S.; Rymen, D.; Hoischen, A.; Wuhrer, M.; Hipgrave-Ederveen, A.; ... ; Lefeber, D.J. 2014
Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of... Show moreTwo colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR = 2.68, p ≤ 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p ≤ 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p ≤ 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p = 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program. Show less
