Nucleic acids analogues, i.e., oligonucleotide N3'-->P5' phosphoramidates and 
N3'-->P5' thio-phosphoramidates, containing 3'-amino-3'-deoxy nucleosides with 
various 2'-substituents were synthesized and extensively studied. These 
compounds resist nuclease hydrolysis and form stable duplexes with complementary 
native phosphodiester DNA and, particularly, RNA strands. An increase in 
duplexes' melting temperature, DeltaT(m), relative to their phosphodiester 
counterparts, reaches 2.2-4.0 degrees per modified nucleoside. 2'-OH- 
(RNA-like), 2'-O-Me-, and 2'-ribo-F-nucleoside substitutions result in the 
highest degree of duplex stabilization. Moreover, under close to physiological 
salt and pH conditions, the 2'-deoxy- and 2'-fluoro-phosphoramidate compounds 
form extremely stable triple-stranded complexes with either single- or 
double-stranded phosphodiester DNA oligonucleotides. Melting temperature, T(m), 
of these triplexes exceeds T(m) values for the isosequential phosphodiester 
counterparts by up to 35 degrees . 2'-Deoxy-N3'-->P5' phosphoramidates adopt 
RNA-like C3'-endo or N-type nucleoside sugar-ring conformations and hence can be 
used as stable RNA mimetics. Duplexes formed by 2'-deoxy phosphoramidates with 
complementary RNA strands are not substrates for RNase H-mediated cleavage in 
vitro. Oligonucleotide phosphoramidates and especially thio-phosphoramidates 
conjugated with lipid groups are cell-permeable and demonstrate high biological 
target specific activity in vitro. In vivo, these compounds show good 
bioavailability and efficient biodistribution to all major organs, while 
exerting acceptable toxicity at therapeutically relevant doses. Short 
oligonucleotide N3'-->P5' thio-phosphoramidate conjugated to 5'-palmitoyl group, 
designated as GRN163L (Imetelstat), was recently introduced as a potent human 
telomerase inhibitor. GRN163L is not an antisense agent; it is a direct 
competitive inhibitor of human telomerase, which directly binds to the active 
site of the enzyme and thus inhibits its activity. This compound is currently in 
multiple Phase-I and Phase-I/II clinical trials as potential broad-spectrum 
anticancer agent.