Nucleoside Di- and Triphosphates as a New Generation of Anti-HIV Pronucleotides. Chemical and Biological Aspects
Round 1
Reviewer 1 Report
This review provides very detail overview on chemical synthesis of modified nucleoside polyphosphates and their important prodrugs as compounds with high potential in therapy of serious viral diseases. The application of nucleoside analogs has led in many cases to a mutation in viral-encoded nucleoside kinase and thus to the formation of resistance. Such loss of activity can be compensated by application of nucleoside polyphosphates protected on phosphorus moieties by suitable groups removable under physiological conditions.
The development of efficient prodrugs of nucleoside polyphosphates is significant but extremely difficult task as also obvious from this review.
Authors submitted well written review - significant contribution to the field of nucleoside and nucleotide chemistry and biology.
Comments:
Lines 75-77. Thymidine kinase converts AZT into AZTMP but not to AZTDP. This latter job belongs to nucleoside monophosphate kinases. Please, clarify this.
Line 574. Fig. 6. Completely wrong chemical structures of adefovir and cidofovir!!!! Please check carefully original paper [105] and correct it.
Line 534. Check …. disappointment … instead of ….. disappointed ….
Line 641. Check …. alkyl …. instead of …. alkil ….
I recommend this review for publication in Applied Sciences but after minor revision.
Author Response
Thank you for your valuable comments and the detailed discussion.
(1) We have clarified the information about the enzyme that is responsible for the conversion of AZTMP into AZTDP (lines 75-77).
(2) We corrected the chemical structures in Figure 6. Also, we removed the numbering of compounds 32a and 32b (line 581).
(3) All typographical errors noticed have been corrected (line 544; line 650, Figure 7).
Reviewer 2 Report
The manuscript consists of two general parts. In the first one (more than half of the manuscript), the synthesis of nucleotides is extensively reviewed (also from the historical point of view), i. e. compounds consisting of a natural or unnatural nucleobase, a sugar unit, mostly ribose, and mono, di- and triphosphate. I. e. there are no polyphosphates as claimed in the topic and throughout the manuscript. This misleading term has to be replaced in all cases! Furthermore, this first part does not contain many innovative facts from the past view years. There are also other previous summaries in this field. The second half of the manuscript deals with Anti-HIV pronucleotides, i. e. it meets the topic. Here, more recent publications are included.
I consider the manuscript as not to be in the utmost leading forefront, but it is easy to read and cană be interesting for scientists entering the field of antiviral pronucleotides. I recommend acceptance of the manuscript after revision, wherein the term polyphosphates is replaced throughout the manuscript. It certainly is also worth mentioning that Alexander Todd awarded the Nobel Prize for his pioneering work in the nucleotide field. At line 358 is better to use the term aryloxy than phenyl group.
Author Response
Thank you for your time and the valuable comments.
(1) We replaced the term polyphosphates throughout the manuscript (also in the title) with di- or triphosphates, depending on the context. In some cases, we have replaced it with the term nucleotides.
(2) In the Conclusion section (lines 815-816) we added information about the 1957 Nobel Prize in Chemistry for Lord Tod.
(3) We changed the term phenyl to aryloxy (line 366).
