![]() ![]() Therefore, the scaffold hopping approach achieved our goal of optimizing NBD-556 from a gp120 agonist to a gp120 antagonist with potent anti-HIV-1 activity. This transformation yielded NBD-11021, which showed a complete reversal of gp120 agonist to gp120 antagonist trait, and it was our first, second-generation inhibitor that showed potent antiviral activity ( Figure 1). However, we successfully converted the oxalamide moiety of NBD-09027 to a pyrrole and kept the other portions in Region I and Region III ( Figure 1) the same as in NBD-09027. This inhibitor showed partial agonist characteristics. Our major success came when we replaced the 2,2,6,6-tetramethylpiperidine scaffold of NBD-556 with a (4-methyl-2-(piperidin-2-ylmethyl)thiazol-5-yl)methanol scaffold and obtained NBD-09027. Most notably, we used the scaffold hopping approach to alter the oxalamide moiety to a diverse scaffold to convert NBD-556 from being a gp120 agonist to an antagonist. Although this was an initial setback for our endeavor to discover gp120 targeted entry inhibitors, we made continuous strides in modifying all three regions of NBD-556 ( Figure 1). However, this inhibitor was later shown to induce HIV-1 infection in CD4 -CCR5 + cells, thereby acting as a gp120 agonist. In 2005, we first reported identifying a small-molecule inhibitor, NBD-556, that targets HIV1 gp120. Among the HIV entry targets, the envelope glycoprotein, gp120, has emerged as a well-validated target, and its inhibition is critical for bringing additional therapy to HIV infections. Several HIV entry targets have been identified and validated as critical players in the AIDS pathology. ![]() This strategy has been pursued in virtually all virus pathologies, including Human Immunodeficiency Virus (HIV). The blockage of these processes prevents virus proliferation and infections. They have developed specific molecular mechanisms and strategies to achieve that. Therefore, all viruses require that their genetic information (DNA or RNA, depending upon the Virus typology) reaches the host cell nucleus for replication. ![]() ![]() Viruses are biological entities that are not capable of self-replicating by themselves, and they require the support of a host cell transcriptional genetic apparatus for their life cycle. ![]()
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