A System of Protein Target Sequences for Anti–RNA–Viral Chemotherapy by Vitamin B6 Conjugate Analogues.

Andreas J. Kesel. Chammünsterstr. 47, D-81827 München (Germany).

Background: The synthesis of retinoid vitamin A-vitamin B6 conjugate analogues from a vitamin B6 coenzyme analogue and putative HIV-1 trans-activating transcriptional regulatory protein Tat antagonist (Z)-5’-O-phosphono-pyridoxylidenerhodanine (B6PR) monosodium salt hemiheptadecahydrate [(Z)-B6PRNa8.5H2O] is discussed here. All-trans retinoic acid (ATRA) is coupled to B6PR by a modified Stork enamine acylation. It results a product library of more than eight compounds, each with at least one intact all-trans or 13-cis vitamin A double bond system. This new retinoid selection could be of further interest in antiviral applications, especially treating conditions caused by RNA viruses like HIV. Material and Methods: This yellow oily concentrate mixture was subjected to matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry (MS), UV/VIS-spectrophotometry, and proton nuclear magnetic resonance spectroscopy (1H-NMR). The chemical structures of six components of the concentrate mixture could be established by combination of these analytical methods. The two main components are 65 % 2‘C,3O-(all-trans retinylidyne)B6PT (B6RA) and 25 % 2‘C-(all-trans retinoyl)B6PT, chemically derived from (5RS)-5-(5‘-O-phosphono-pyridoxyl)-2,4-thiazolidinedione (B6PT). Results: The synthesis of the nucleobase/nucleotide-pyridoxoid analogues (E)-N6-(5‘-O-phosphono-pyridoxylidene)adenine (B6AD), (E)-N6-pyridoxylideneadenine, and (E)-N6-pyridoxylideneadenosine-5‘-monophosphoric acid is discussed here. The yellow adenine Schiff base analogue with pyridoxal and the yellow adenosine nucleotide Schiff base analogue with pyridoxal exist in equilibrium mixtures with their white cyclic hemiaminals. In the yellow adenine Schiff base with pyridoxal 5’-phosphate the cyclization is blocked by the phosphate group. The compounds can be crystallized readily as monosodium salts, free zwitterionic acids or hydrochlorides. The three new adenine nucleobase and adenosine nucleotide vitamin B6-conjugate analogues are promising candidates for influencing nucleic acid metabolism in viral infections and cancer. Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA, B6AD is proposed to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and B6AD. In addition, candidate targets of B6RA and B6AD could be adsorption, transcription and/or viral RNA replication of RNA viruses like Picornaviridae (poliovirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus) and Reoviridae (human rotavirus). The antiviral scope of B6RA/B6AD may be related to the broad-spectrum anti-RNA-viral virustatic ribavirin.