ABSTRACT
Regions of possible interaction between remantadine and transmembrane M2 protein are revealed by analysis of amino acid substitutions in remantadine- and deutiforin-resistant influenza viruses. The major region includes 5-6 amino acid residues at position 25-31, partially involving the premembrane region and the first position of a hydrophobic membrane-associated domain. The proposed model action of remantadine and its derivatives suggests that remantadine is included into the cell membrane lipid bimolecular layer by its adamantane share and its positively charged NH2-group is exposed to the cell surface. This allows remantadine and its analog to be regarded as molecular "hindrances" for viral particle decapsidation and budding.
Subject(s)
Adamantane/pharmacology , Antiviral Agents/pharmacology , Adamantane/analogs & derivatives , Adamantane/antagonists & inhibitors , Amino Acid Sequence , Antiviral Agents/analogs & derivatives , Antiviral Agents/antagonists & inhibitors , Base Sequence , Drug Resistance, Microbial/genetics , Genes, Viral/drug effects , Genes, Viral/genetics , Influenza A virus/drug effects , Influenza A virus/genetics , Models, Molecular , Molecular Sequence Data , Mutation , Structure-Activity Relationship , Viral Matrix Proteins/drug effects , Viral Matrix Proteins/geneticsABSTRACT
Several analogues of a new lead for anti-HIV-1 agents [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-thymine] -3'-spiro-5''-(4''-amino-1'',2''-oxathiole 2'',2''-dioxide) (TSAO) modified at positions N-3, O-4 and C-5 of the thymine moiety, have been prepared and evaluated as inhibitors of HIV-1 replication. A new stereoselective synthetic procedure is described. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with pyrimidine bases, followed by treatment with Cs2CO3 afforded stereoselectively, beta-D-ribofuranosyl-3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO derivatives. Only those analogues having a tBDMSi group at both the C-5' and C-2' positions of the ribose moiety showed potent anti-HIV-1 activity. The activity ranged from 0.060 microM to 1.0 microM. Introduction of an alkyl or alkenyl function at N-3 of the thymine ring markedly decreased cytotoxicity without affecting the antiviral activity. While markedly active against HIV-1, the TSAO derivatives had no activity against HIV-2 or SIV. They represent the first example of nucleoside analogues with an intact ribose moiety that discriminate between HIV-1 and other retroviruses.
