Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor.

One of the most critical requirements of the infection of the human immunodeficiency virus type 1 (HIV-1) is the interaction of its surface envelope glycoprotein gp120 with the cellular receptor CD4, which initiates virus entry to cells. Therefore, envelope glycoprotein gp120 has been validated as a potential target to develop HIV-1 entry inhibitors. Here we report the evaluation of a novel non-natural amino acid, termed 882376, reported earlier as a precursor of a CD4-mimetic miniprotein, as HIV-1 entry inhibitor. 882376 showed HIV-1 inhibitory activity against a large panel of primary isolates of different subtype. Moreover, genotyping of 882376 resistant HIV-1 virus revealed three amino acid substitutions in the gp120 including one in the CD4 binding site suggesting that this molecule may bind to gp120 and prevent its binding to CD4. Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4. The unnatural amino acid, 882376, is expected to serve as a lead for further optimization to more potent HIV-1 entry inhibitors.

Rapid Visual Screening and Programmable Subtype Classification of Ebola Virus Biomarkers.

The massive outbreaks of the highly transmissible and lethal Ebola virus disease were caused by infection with one of the Ebolavirus species. It is vital to develop cost-effective, highly sensitive and selective multitarget biosensing platforms that allow for both the detection and phenotyping. Here, a highly programmable, cost-efficient and multianalyte sensing approach is reported that enables visual detection and differentiation of conserved oligonucleotide regions of all Ebolavirus subtypes known to infect human primates. This approach enables the detection of as little as 400 amols (24 × 106 molecules) of target sequences with the naked eye. Furthermore, the detection assay can be used to classify four virus biomarkers using a single nanoprobe template. This can be achieved by using different combinations of short single stranded initiator molecules, referred to as programming units, which also enable the simultaneous and rapid identification of the four biomarkers in 16 different combinations. The results of 16 × 5 array studies illustrate that the system is extremely selective with no false-positive or false-negative. Finally, the target strands in liquid biopsy mimics prepared from urine specimens are also able to be identified and classified.