Marvin H. Caruthers

Bio-Analytical Chemistry, Bio-Inorganic Chemistry, Gene Expression and Regulation, Genetics and Chemical Biology, and Nucleic Acids. Professor Caruthers’ laboratory has also pioneered the synthesis of many new nucleic acid analogues that have found applications in the nucleic acid diagnostic and therapeutic areas. Two of these analogues will be discussed. Several years past we developed methodologies leading to the chemical synthesis of oligonucleotides having phosphonoacetate internucleotide linkages [Solid Phase Chemical Synthesis of Phosphonoacetate and Thiophosphonoacetate Oligodeoxynucleotides. D. J. Dellinger, D. M. Sheehan, N. Christensen, J. G. Lindberg and M. H. Caruthers. J. Am. Chem. Soc. 125, 940 (2003)] and the development of this synthesis strategy was quickly followed by a series of biological and biochemical studies of these phosphonoacetate and thiophosphonoacetate analogues [Biochemical Properties of Phosphonoacetate and Thiophosphonoacetate Oligodeoxynucleotides. D. M. Sheehan, B. Lunstad, C. M Yamada, B. Stell, M. H. Caruthers and D. J. Dellinger, Nucleic Acids Res. 31, 4109 (2003)]. Recently the effects of various chemical modifications in guide RNAs (gRNAs) at defined positions and combinations have been investigated (Phosphonoacetate Modifications Enhance the Stability and Editing Yields of Guide RNAs for Cas9 Editors. Daniel E. Ryan, Tamar Diamant-Levi, Israel Steinfeld, David Taussig, Savita Visal-Shah, Suhani Thakker, Benjamin D. Lunstad, Robert J. Kaiser, Ryan McCaffrey, Michael Ortiz, Justin Townsend, William R. W. Welch, Mandeep Singh, Bo Curry, Douglas J. Dellinger, and Laurakay Bruhn. These investigators found that 2′-O-methyl-3′- phosphonoacetate (MP) modifications were substantially more effective than 2′-O-methyl-3′-phosphorothioate (MS) modifications at the 3′ ends of single-guide RNAs (sgRNAs) towards promoting high editing yields, in some instances an order of magnitude higher in human cells