Privileged Structures Meet Human T-Cell Leukemia Virus-1 (HTLV-1): C₂-Symmetric 3,4-Disubstituted Pyrrolidines as Nonpeptidic HTLV-1 Protease Inhibitors

Abstract

3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 protease (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, to the best of our knowledge, the most potent nonpeptidic inhibitor of HTLV-1 PR described so far. The X-ray structures of two representatives bound to HTLV-1 PR were determined, and the structural basis of their affinity is discussed.

What Are We Missing? The Detergent Triton X‐100 Added to Avoid Compound Aggregation Can Affect Assay Results in an Unpredictable Manner

“…[10] In addition, anX -ray structure of 1 in complex with the relatedH TLV-1p rotease was recently published, also indicating as pecific binding to the protein (PDB ID: 4YDF). [17] In contrast to 1,s imilar K i values for 2 at assay conditions withouta dditive and 0.01 %T riton X-100 were obtainedt hus classifying this derivativea satrue positive. However,aprogressive decrease in inhibition was observed when the Triton X-100 concentration was gradually increased to 0.1 %, thereby leadingt oa na lmostc omplete loss of the inhibitory activity of 2 ( Figure 3).…”

Synthesis of bioactive fluoropyrrolidinesviacopper(i)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

“…[18][19][20][21][22] On the other hand, enantioenriched pyrrolidinyl groups, which are important building blocks in many biologically active natural alkaloids and pharmaceuticals, have attracted much attention in last decades. [23][24][25][26][27][28] The transition-metal-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with electron deficient alkenes represents one of the most powerful methods for the stereocontrolled synthesis of these molecules. [29][30][31][32][33][34] Considering the crucial property of fluorine atoms, incorporating fluorine atoms into heterocycle rings in chiral pyrrolidine derivatives would change their bioactivities to a great extent.…”

Comparative study of the unbinding process of some HTLV-1 protease inhibitors using Unbiased Molecular Dynamics simulation

“…Unfortunately, this drug failed to be used to eradicate HTLV-1 [10]. After being frustrated with AIDS drugs, this team, in 2015, succeeded in synthesizing ten inhibitors that contain the most potent nonpeptidic inhibitor of HTLV-1 protease up to now [11].…”