A re-evaluation of the biosynthetic hypothesis of the manzamine natural products is discussed. In addition to considering its unified origins with other marine alkaloids, several other plausible biosynthetic hypotheses are critically evaluated.
Aptamers composed of mirror-image L-(deoxy)ribose nucleic acids, referred to as L-aptamers, are a promising class of RNAbinding reagents. Yet, the selectivity of cross-chiral interactions between L-aptamers and their RNA targets remain poorly characterized, limiting the potential utility of this approach for applications in biological systems. Herein, we carried out the first comprehensive analysis of cross-chiral L-aptamer selectivity using a newly developed "inverse" in vitro selection approach that exploits the genetic nature of the D-RNA ligand. By employing a library of more than a million target-derived sequences, we determined the RNA sequence and structural preference of a model L-aptamer and revealed previously unidentified and potentially broad off-target RNA binding behaviors. These results provide valuable information for assessing the likelihood and consequences of potential offtarget interactions and reveal strategies to mitigate these effects. Thus, inverse in vitro selection provides several opportunities to advance L-aptamer technology.
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