Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The MS3 aptamer selectively binds and modulates mutant huntingtin (mHTT).
• MS3 aptamer exhibits a propensity to form complex G-quadruplex structures and multimeric aggregates.

Purpose of the Study:

• To design and evaluate physicochemical and biological properties of two truncated MS3 aptamer analogues.
• To assess the bioactivity of shorter MS3-derived aptamers compared to the parent MS3 aptamer.

Main Methods:

• Truncation of the 36-mer MS3 aptamer to create 33-mer (MS3-33) and 17-mer (MS3-17) analogues.
• Physicochemical characterization using UV, CD, DSC, and gel electrophoresis.
• In vitro testing on SH-SY5Y cells and in vivo testing on a *Drosophila* Huntington's disease model.

Main Results:

• Detailed physicochemical characterization of the novel G-quadruplex-forming aptamers MS3-33 and MS3-17.
• MS3-33 and MS3-17 demonstrated improved bioactivity compared to the original MS3 aptamer.
• Shorter aptamers showed enhanced performance in both in vitro and in vivo models of Huntington's disease.

Conclusions:

• Truncated MS3 aptamers (MS3-33 and MS3-17) retain G-quadruplex forming properties.
• These shorter aptamers exhibit enhanced bioactivity for targeting mutant huntingtin.
• MS3-33 and MS3-17 represent promising therapeutic candidates for Huntington's disease.