An oligo- or polynucleotide analogue having one or more structures of the general formula where B is a pyrimidine or purine nucleic acid base, or an analogue thereof,
 
is disclosed. The use of this analogue provides an oligonucleotide analogue antisense molecule, which is minimally hydrolyzable with an enzyme in vivo, has a high sense strand binding ability, and is easily synthesized.

Bicyclonucleoside and oligonucleotide analogues

The present invention is substituted amines of formula (X) useful in treating Alzheimer's disease and other similar diseases.

Compounds to treat Alzheimer's disease

Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster.

The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise.

https://www.pnas.org/content/pnas/93/4/1648.full.pdf

Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors

Recent advances in L-nucleosides: chemistry and biology.

A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereospecifically achieved starting from 1,2-isopropylidene-D-xylofuranose (10) An efficient two-step reduction of the anomeric center of bis-acetate 18 involved formation of the chloride intermediate 19, followed by diisobutylaluminum hydride reduction Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anions Several members of this new class of compounds possess activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV) Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpesviruses, in particular, HSV-1 and HSV-2 Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 microM Although the antiherpetic activity in vitro of 7 is less than that of acyclovir (1), compound 7 displays superior efficacy in mouse model infections The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selective activity against HSV-1 and VZV, with no cytostatic effect on WI-38 cell growth at > 800 microM Compound 8 is active against simian varicella virus and is efficacious in the corresponding monkey model

Synthesis and antiviral activity of novel isonucleoside analogs

A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.

Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.

Aminodiol HIV Protease Inhibitors. Part 1. Design, Synthesis, and Preliminary SAR.

Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1′ Compounds: Correlation Between Lipophilicity and Cytotoxicity.

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Synthesis and antiviral activity of novel isonucleoside analogs

Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.

Aminodiol HIV Protease Inhibitors. Part 1. Design, Synthesis, and Preliminary SAR.

Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1′ Compounds: Correlation Between Lipophilicity and Cytotoxicity.