I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman's group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2',3'-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections.
Benzo/heterothiadiazine dioxides have been identified as important fused heterocyclic systems possessing a broad spectrum of biological activities and potential pharmacological applications. Recently, a large number of structurally novel compounds derived from these heterocycle scaffolds were identified as antiviral agents. Especially, substituted benzo/heterothiadiazine dioxide derivatives have been shown to inhibit the replication of HCMV, VZV, HCV and HIV. Of particular interest, some potent HCV polymerase inhibitors possess a benzothiadiazine dioxide scaffold, which is critical for the anti-HCV potency through strong hydrogen bond formation of the SO(2)NH group with the active site of the enzyme, as shown by X-ray crystallography. Also, some compounds belonging to the benzothiadiazine dioxide class have been found to be potent antiviral agents against HCMV and VZV. Moreover, some novel heterothiadiazine dioxide derivatives have been synthesized and evaluated as potential HIV inhibitors with lower toxicity and/or increased activity against drug-resistant virus strains. No systematic review is available in the literature on these thiadiazine derivatives in the design of potent antiviral inhibitors. In this article, we review the recent advances in the antiviral profile of this kind of compounds, as well as the impact of structural modifications and the structure-activity relationship (SAR).
Abstract 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), the prototype compound of a well-defined structural class of potent and selective anti-retroviral agents, was found to be endowed with long-lasting and dose-dependent differentiation-inducing properties in human erythroleukemia K562 cell cultures.
John Charles Martin should be remembered as a visionary medicinal chemist who was involved in the coinvention, development, or management of many FDA-approved antiviral drugs such as ganciclovir, stavudine, didanosine, cidofovir, oseltamivir, adefovir dipivoxil, tenofovir disoproxil fumarate, tenofovir alafenamide, sofosbuvir, and remdesivir.
Coupling of terminal alkynes with 5-iodo-1-(2,3,5-tri-O-p-toluyl-beta-D-arabinofuranosyl)uracil and 5-iodo-3',5'-di-O-p-toluyl-2'-deoxyuridine proceeded readily in triethylamine with catalytic quantities of bis(triphenylphosphine)-palladium(II) chloride and copper(I) iodide. The resulting products were deprotected to give 5-alkynyl-1-beta-D-arabinofuranosyluracil and 5-alkynyl-2'-deoxyuridine nucleosides. The 5-ethynyl, followed by 5-propynyl, products had the highest antiviral potency, with the 2'-deoxy derivatives being more effective than the arabinosyl compounds. Activity was weak at hexynyl and disappeared at heptynyl. Inclusion of an omega-hydroxy function diminished the antiviral effect. None of the 5-alkynyluracil nucleosides tested had sufficient selectivity to qualify as a candidate antiviral drug. Several of the compounds exerted an inhibitory action on thymidylate synthetase, with 5-ethynyl-2'-deoxyuridine being the most cytotoxic against L1210 cells.
Topical administration of 0.1% or 1% chloroethyldeoxyuridine eyedrops caused a significant reduction in the severity of experimental herpes simplex iritis and stromal keratitis in rabbits. The healing effect caused by chloroethyldeoxyuridine was comparable to that obtained with 0.1% and 0.5% bromovinylde-oxyuridine eyedrops. The drug levels achieved in the anterior chamber fluid following topical application of 1% eyedrops of [2-14C]CEDU, a radiolabelled analogue of chloroethyldeoxyuridine, were well above the minimum concentration (0.1 microgram/mL) required for inhibition of herpes simplex virus type 1 replication. The beneficial effects of chloroethyldeoxyuridine on stomal keratitis and iritis appear consistent with its efficient penetration through the cornea.
The acyclic nucleoside phosphonates [HPMPC (cidofovir), PMEA (adefovir) and PMPA] have proved to the effective in vitro (cell culture systems) and in vivo (animal models, clinical studies) against a wide variety of DNA virus and retrovirus infections: i.e., HPMPC against herpesvirus (herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus types 6, 7, and 18), polyoma-, papilloma-, adeno-, and poxvirus (vaccinia virus, molluscum contagiosum virus) infections; PMEA against herpesvirus, hepadnavirus (human hepatitis B virus) and retrovirus (human immunodeficiency virus type 1 and 2, simian immunodeficiency virus, and feline immunodeficiency virus) infections; and PMPA against both hepadna- and retrovirus infections.
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