HIV inhibitors
Inventors
RODNINA-WINTERMEYER, Marina V. • KORNIY, Natalia • SAMATOVA, Ekaterina • PESKE, Frank
Assignees
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Publication Number
US-12594253-B2
Publication Date
2026-04-07
Expiration Date
Abstract
The present invention relates to a compound comprising of the nucleotide sequence UAA or TAA and a binding site for the covalent attachment of leucine (Leu), wherein said compound is recognized by a ribosome, for use in medicine.
Core Innovation
The invention relates to an anti-HIV strategy positioned to reduce HIV gag-pol Δ1 programmed ribosomal frameshifting by using ribosome-recognized UAA/TAA-containing carrier compounds that provide leucine availability to modulate frameshift efficiency. The carrier is described as a UAA or TAA nucleotide-based compound covalently linked to a leucine-binding site, and it supports ribosome recognition in the translation context of HIV gag-pol Δ1 programmed ribosomal frameshifting.
A key aspect is using tRNALeu(UAA) derivatives that differ from human wild-type tRNALeu(UAA) through stem-region base sequence mutations and/or modifications of the ribose and/or phosphate portions. Stem-region changes are described as substitutions and/or deletions, and the ribose/phosphate modifications are selected from 2′-O-methyl, 2′-deoxy, 2′-fluoro, thiophosphate, LNA, and PNA, with the purpose of adjusting stability and cellular uptake while maintaining ribosome recognition.
The document further states that the approach extends beyond HIV to infections with SIV and Alphaviruses, including the described observation that Alphavirus (SFV 6K) frameshifting exhibits Leu-tRNALeu(UUA)-dependent switching between Δ1 frameshift products. The disclosed mechanism is supported by reported findings that leucine-tRNA concentration modulates Δ1 frameshifting efficiency, including the use of native human aa-tRNA as a confirming basis for modulation.
Claims Coverage
The relevant portion contains one independent claim that covers methods of treating or ameliorating infections with HIV, SIV, an Alphavirus and/or AIDS in a subject by administering a modified tRNALeu(UAA). The claim includes two alternative inventive features: stem-region sequence mutations in the tRNALeu(UAA) and/or specified ribose and/or phosphate modifications of the tRNALeu(UAA).
Treating HIV/SIV/Alphavirus infection or AIDS by administering a modified tRNALeu(UAA)
Administering a tRNALeu(UAA) to a subject for treating or ameliorating infection with HIV virus, SIV virus, an Alphavirus and/or AIDS.
Stem-region mutated tRNALeu(UAA) differs from human wild-type by substitutions or deletions
The administered tRNALeu(UAA) differs from any human wild-type tRNALeu(UAA) by at least one up to ten mutations of the base sequence in a stem region, wherein each mutation is a substitution or deletion.
Ribose and/or phosphate modified tRNALeu(UAA) using specified modification classes
The administered tRNALeu(UAA) comprises at least one modification of a ribose and/or of a phosphate, wherein the modification is selected from 2′-O-methyl, 2′-deoxy, 2′-fluoro, thiophosphate, LNA, and PNA.
Overall, the independent claim scope centers on delivering a tRNALeu(UAA) that either differs from human wild-type in its stem-region sequence via substitutions or deletions, up to ten, or contains specified ribose and/or phosphate modifications, for treating or ameliorating HIV/SIV/Alphavirus infection and/or AIDS in a subject.
Stated Advantages
Reduces HIV gag-pol Δ1 programmed ribosomal frameshifting by leveraging leucine availability from a UAA/TAA-containing construct.
Modulates frameshifting efficiency in a concentration-dependent manner.
Supports Leu-tRNALeu(UUA)-dependent switching between Δ1 frameshift products in Alphavirus frameshifting.
Documented Applications
Treating or ameliorating an infection with HIV virus, with SIV virus, with an Alphavirus and/or AIDS in a subject.
Alphavirus frameshifting, including SFV 6K frameshifting.
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