Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate

Abstract

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof-of-concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA.

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

“…In addition, we recognize the importance of linker addition and the attachment point to the NNRTI entity from our previous study with the TIBO bifunctional series with decreased antiviral activities compare to 8-Cl-TIBO. 33 Alignment of the RT/8-Cl-TIBO structure 39 with the RT/TMC278 structure 35 shows that the chlorine atom on the benzene ring of 8-Cl-TIBO projects into the base of the hydrophobic tunnel to some extent, where the cyanovinyl substituent of wing I of TMC278 binds in a subpocket generated by residues F227 and W229. Although the functionalization at the 8-Cl position could point toward the active site of the enzyme, our results demonstrated that placing a PEG tether at this position severely impairs potency by 2000-fold.…”

“…Although the functionalization at the 8-Cl position could point toward the active site of the enzyme, our results demonstrated that placing a PEG tether at this position severely impairs potency by 2000-fold. 33 This result implies that either the 8-Cl-TIBO lacks flexibility or the neighboring residues in this region are perhaps less flexible than the residues lining the hydrophobic tunnel accepting the cyanovinyl substituent of TMC278. Therefore, the present study focused on utilizing d4T-4PEG-TMC as our bifunctional prototype.…”

“…33 Although we demonstrated the incorporation of the triphosphate form of an N3-substituted d4T-6PEG-TIBO bifunctional compound, the use of 8-Cl-TIBO as a pharmacophore for our bifunctional inhibitor was less than ideal since the addition of a 6PEG alcohol at the 8-position substantially diminished the antiviral activity. 33 …”

Luminescent Organogels Generated from Nucleosides Functionalized with Carbazole: Synthesis and Probing for F–

“…The synthetic routes for nucleolipid derivatives ( UC8 , UC12 and UC16 ) are shown in Scheme . First, the carbazole boronate ester 1 and the 5‐iodo‐uridine 2 were synthesized according to the previous reports , . The Suzuki coupling reactions between compounds 1 , bearing alkyl groups with different length, and compound 2 in the presence of Pd(dppf) 2 Cl 2 afforded UC8 , UC12 , and UC16 , respectively.…”

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

“…The same group also reported the preparation and biochemical assay of another bifunctional RT inhibitor 44 (d4T-6PEG-TIBO conjugate) utilizing d4T and a TIBO derivative linked by a PEG linker (Figure ). However, its effectiveness was limited . Even so, this strategy should be applicable to other proteins with multiple binding sites.…”