We have recently discovered a novel ring-expanded nucleoside (REN) that potently inhibits both the human immunodeficiency virus (HIV) as well as the hepatitis C virus (HCV) in vitro with IC50 values in the micromolar and nanomolar ranges, respectively, for the two viruses, with little toxicity, if any, to the host cells. Since HCV is a major co-infection in the HIV-infected individuals, the discovery of a compound capable of dual viral inhibition of HIV and HCV, the two dreaded viruses eliciting current national and international health concern, is biomedically significant and merits further exploration. This proposal specifically focuses on investigation of the mechanism of anti-HIV activity of the compound. Since nothing is known on this front, we intend to use this R21 application to quickly acquire some important preliminary data concerning the stage of the viral life cycle that is being affected by the REN. These preliminary data would serve as the basis for a subsequent R01 application for an in-depth investigation of the mechanism of anti-HIV activity specific to the stage of the viral life cycle, and in turn, for the extensive SAR studies. The important questions to be addressed in here include: (a) whether the REN exerts its effect on the virus production or virus inhibition, (b) whether it inhibits the early events in the viral life cycle, including the viral entry, reverse transcription, nuclear localization and integration, or later events, including transcription of the integrated provirus, nuclear export, assembly and particle production, (c) whether in vivo phosphorylation of the REN is necessary for it to be active, considering that the active forms of many, if not all, nucleoside analogues are known to be their corresponding mono-, di-, or triphosphate derivatives, and (d) whether the mechanism of activity of REN involves incorporation into nucleic acids via their 5'-triphosphate derivatives and subsequent chain termination, considering that many antiviral nucleoside analogues are known to operate by this mechanism. In addition, we will synthesize a few selected analogues of the lead compound to see if the antiviral activity could be further enhanced. This includes (a) synthesis of the ribose analogue of the lead REN, and (b) extending the alkyl chain at position-6 by a few more carbon atoms. Finally, we will investigate if the leading REN as well as its analogues are effective against the resistant HIV mutants. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21AI071802-01S1
Application #
7274009
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Conley, Tony J
Project Start
2006-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$48,478
Indirect Cost
Name
University of Maryland Balt CO Campus
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
061364808
City
Baltimore
State
MD
Country
United States
Zip Code
21250
Zhang, Ning; Zhang, Peng; Baier, Andrea et al. (2014) Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring system. In vitro results and implications. Bioorg Med Chem Lett 24:1154-7
Ujjinamatada, Ravi K; Phatak, Pornima; Burger, Angelika M et al. (2008) Inhibition of adenosine deaminase by analogues of adenosine and inosine, incorporating a common heterocyclic base, 4(7)-amino-6(5)H-imidazo[4,5-d]pyridazin-7(4)one. J Med Chem 51:694-8
Yedavalli, Venkat S R K; Zhang, Ning; Cai, Hongyi et al. (2008) Ring expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication. J Med Chem 51:5043-51
Kumar, Raj; Ujjinamatada, Ravi K; Hosmane, Ramachandra S (2008) The first synthesis of a novel 5:7:5-fused diimidazodiazepine ring system and some of its chemical properties. Org Lett 10:4681-4
Zhang, Peng; Zhang, Ning; Korba, Brent E et al. (2007) Structure-activity relationship studies on anti-HCV activity of ring-expanded ('fat') nucleobase analogues containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system. Bioorg Med Chem Lett 17:2225-8
Zhang, Peng; Zhang, Ning; Buckwold, Victor E et al. (2007) Chemical and biological effects of substitution of the 2-position of ring-expanded ('fat') nucleosides containing the imidazo[4,5-e][1,3]diazepine-4,8-dione ring system: the role of electronic and steric factors on glycosidic bond stability and anti-HCV a Bioorg Med Chem 15:4933-45
Ujjinamatada, Ravi K; Baier, Andrea; Borowski, Peter et al. (2007) An analogue of AICAR with dual inhibitory activity against WNV and HCV NTPase/helicase: synthesis and in vitro screening of 4-carbamoyl-5-(4,6-diamino-2,5-dihydro-1,3,5-triazin-2-yl)imidazole-1-beta-D-ribofuranoside. Bioorg Med Chem Lett 17:2285-8
Ujjinamatada, Ravi K; Bhan, Anila; Hosmane, Ramachandra S (2006) Design of inhibitors against guanase: synthesis and biochemical evaluation of analogues of azepinomycin. Bioorg Med Chem Lett 16:5551-4