The 1,3-dipolar cycloaddition of polymer-supported azomethine ylides to dipolarophiles gave pyrrolidine derivatives in good yields. The azomethine ylides were generated from resin-bound alpha-silylimines via a 1,2-silatropic shift. The features of this method are not only a traceless synthesis but also a unique solid-phase route to pyrrolidines with extensive diversity. [reaction: see text]

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HIV-1 integrase (IN) is an essential enzyme for viral replication. Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 IN inhibitors and a potential new class of antiretrovirals. In this report, we identified a novel NCINI, JTP-0157602, with an original scaffold. JTP-0157602 exhibited potent antiviral activity against HIV-1 and showed a serum-shifted EC 90 of 138 nM, which is comparable to the FDA-approved IN strand transfer inhibitors (INSTIs). This compound was fully potent against a wide range of recombinant viruses with IN polymorphisms, including amino acids 124/125, a hot spot of IN polymorphisms. In addition, JTP-0157602 retained potent antiviral activity against a broad panel of recombinant viruses with INSTI-related resistant mutations, including multiple substitutions that emerged in clinical studies of INSTIs. Resistance selection experiments of JTP-0157602 led to the emergence of A128T and T174I mutations, which are located at the lens epithelium-derived growth factor/p75 binding pocket of IN. JTP-0157602 inhibited HIV-1 replication mainly during the late-phase of the replication cycle, and HIV-1 virions produced by reactivation from HIV-1 latently-infected Jurkat cells in the presence of JTP-0157602 were non-infectious. These results suggest that JTP-0157602 and analog compounds can be used to treat HIV-1 infectious diseases. IMPORTANCE Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 integrase (IN) inhibitors that bind to the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. NCINIs are expected to be a new class of anti-HIV-1 agents. In this study, we present a novel NCINI, JTP-0157602, which has potent activity against a broad range of HIV-1 strains with IN polymorphisms. Furthermore, JTP-0157602 shows strong antiviral activity against IN strand transfer inhibitor-resistant mutations, suggesting JTP-0157602 and its analogs are potential agents to treat HIV-1 infections. Structural modeling indicated that JTP-0157602 binds to the LEDGF/p75 binding pocket of IN, and the results of in vitro resistance induction revealed the JTP-0157602-resistance mechanism of HIV-1. These data shed light on developing novel NCINIs, which exhibit potent activity against HIV-1 with broad IN polymorphisms and multi-drug resistant HIV-1 variants.

The fragment molecular orbital (FMO) method is a fast quantum-mechanics method that divides systems into pieces of fragments and performs ab initio calculations. The method has been expected to improve the accuracy of describing protein-ligand interactions by incorporating electronic effects. In this article, FMO calculation with solvation methods were applied to the affinity prediction at the ATP-binding site of PDHK4. As the ionized aspartic acid lies at the center and is involved in the complex hydrogen bond networks, this system has turned out to be a difficult target to describe by traditional molecular-mechanics method. In the FMO calculation with the polarizable continuum model (PCM) solvation method, a considerable amount of charge ( 0.27e) was transferred from the ionized aspartate to the surrounding residues. We found that using FMO with the PCM solvation method was important to increase the correlation, and by incorporating the ligand deformation energy, the correlation was improved to R 0.81 for whole twelve compounds and R 0.91 without one outlier compound.

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