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Peptidyl-oligonucleotide conjugates: from single and dual conjugates
to different types of bulge-inducing conjugates
Yaroslav Staroseletz
1
, Bahareh Amirloo
2
, Elena Bichenkova
2
, Marina Zenkova
1
1
Institute of Chemical Biology and fundamental medicine 
2
School of pharmacyManchester University
Peptidyl-oligonucleotide conjugates (POC) are a group of artificial RNases targeting RNA 
of choice in sequence-specific manner. POCs utilize short amphiphilic peptide, consisting of 
alternating leucine and arginine residues as a catalytic group: (LR)4G and (LRG)2. DNA oligo-
nucleotide serves as recognition motif of POC. The length of recognition motif has to ensure 
strict specificity of RNA cleavage and to provide binding of POC with RNA target. 
Three series of POCs, based on three conceptual foundations were targeted against TΨC- 
loop of yeast tRNA
Phe.
The first series includes 5 single conjugates (SC), characterized by 
peptide attached to 5’-end of 17-mer oligodeoxynucleotide via zero-length linker and differed 
by peptide structure [1]. The conjugates of the second series (dual conjugates, DC) place the 
catalytic peptide in-between two oligodeoxynucleotide recognition motifs [2]. These conju-
gates vary in all elements of structure: peptide, oligonucleotide and linker. The conjugates 
of the third series (bulge inducing conjugates, BC) place the catalytic peptide at an internal 
position within an oligonucleotide sequence opposite to a bulge formed in RNA target upon 
hybridization with POC. 
Each series of POCs was variegated, including totally inactive and catalytically active POCs 
with several medium variants. Cleavage activity of the conjugate depends on such factors as 
peptide structure, linker length and oligonucleotide sequence. Two subseries of BC appeared 
to be totally different as cleaving agents. BCs with peptide attached with amino-hexyl linker via 
C8-adenosine didn’t cleave tRNA
Phe
. In contrast attachment of peptide to C1’ of deoxyribose 
(either α-, or β-anomer) provides cleavage activity to the conjugate. 
Conjugates-leaders demonstrated 100% cleavage extent of tRNA
Phe
in time diapason from 
4 to 48 h at 20 μM POCs and 1 μM tRNA
Phe
concentration. Several types of cleavage pattern 
were revealed. Conjugates cleave both at target site region 
61
CACAG
65
and outside this region 
with either G-X or Pyr-X specificity. 
1. Williams A., Staroseletz Y., Zenkova M.A., Jeannin L., Aojula H., Bichenkova E. peptidyl-
oligonucleotide conjugates demonstrate efficient cleavage of RNA in a sequence-specific 
manner. Bioconjugate Chem. – 2015. – V. 26. p 1129–1143.
2. Staroseletz Y., Williams A., Burusco K., Alibay I., Vlassov V., Zenkova M., Bichenkova E. 
‘Dual’ peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic 
cleavage of RNA.. Biomaterials. – 2016. – V. 112. - p 44–61.
This work received financial support from Russian Science Foundation grant № 19-14-00250 and 
Russian State funded budget project of ICBFM SB RAS № AAAA-A17-117020210024-8.

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Всероссийская мультиконференция с международным участием «Биотехнология – медицине будущего»
29 июня - 2 июля 2019 г., г. Новосибирск, Россия
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