Zinc Finger Inhibitor 2015

From Bruce E. Torbett • David S. Goodsell Douglas • D. Richman

The Future of HIV-1 Therapeutics   

  Due to their potent antiviral activity in vitro, several attempts were made to evaluate
the potential therapeutic use of zinc ejectors in vivo. To our knowledge, only two
zinc ejectors, namely ADA and benzisothiazolone, were tested in clinical studies.
Due to its toxicity, assays with the second compound were rapidly stopped (Turpin
2003). Preclinical tolerance assays showed that oral doses of 1.5 g ADA daily for
1 month were well tolerated, with no evidence of adverse effects (Vandevelde et al.
1996). Then, ADA was administrated three times daily during 3 months in addition
to other antiviral therapy to fifteen individuals with advanced AIDS within a Phase
I/II clinical trial.

Library of Congress Control Number: 2015937951 Springer Cham Heidelberg New York Dordrecht London © Springer International Publishing Switzerland 2015

US government) (click on NIAID searchable database and submit Azodicarbonamide) http://www.niaid.nih.gov/

Vandevelde M, Witvrouw M, Schmit JC, Sprecher S, De Clercq E, Tassignon JP ADA,

a potential anti-HIV drug. AIDS Res Hum Retroviruses. 1996 May 1; 12(7):567-8 ADA , a Potential Anti-HIV Drug. ADA (l,l'-azobisformamide) is the abbreviated name for an azoic compound with the following structural formula (MW = 116.08). As formal clinical studies are about to start in AIDS patients with ADA, we report for the first time pre-clinical results of studies showing that ADA is inhibitory to the replication of HIV-1 and is a virucidal agent in vitro.

H2N—OC—N==N—CO—NH2

In conclusion, ADA may be considered as a potential anti-HIV drug. It may be targeted at a post-transcriptional stage of retroviral replication. It has a very low in vivo toxicity. Thus, ADA, suitably formulated pharmaceutically, represents an in­teresting new investigational compound for the treatment and/or prophylaxis of AIDS in man. ADA could be used in combina­tion with RT inhibitors (DDI, d4T). M. Vandevelde Hubriphar SA Brussels. Belgium. M. Witvrouw J.C. Schmit AIDS Laboratory Rcga Institute of Medical Research Kalhotieke Universiteit Leuven Leuven, Belgium S. Sprecher Institut Pasteur Brussels, Belgium http://www.ncbi.nlm.nih.gov/

Rice, W.G., Turpin, J.A., Huang, M., Clanton, D., Buckheit, R.W., Covell, D.G.,

Wallquist, A., McDonnell, N.B., DeGuzman, R.N., Summers, M.F., Zalkow, L., Bader, J.P., Haugwitz, R.D. and Sausville, E.A. Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein without affecting cellular zinc finger proteins. Nature Medicine 3, 341-345 (1997). http://www.ncbi.nlm.nih.gov/

Huang M, Maynard A, Turpin JA, Graham L, Janini GM, Covell DG, Rice WG Anti-HIV agents

that selectively target retroviral nucleocapsid protein zinc fingers  J Med Chem. 1998 Apr 23;41 (9):1371-81 http://www.ncbi.nlm.nih.gov/

Maynard, A., Huang, M., Rice, W.G., and Covell, D.G.

Reactivity of the HIV-1 NCp7 zinc finger domains from the perspective of density-functional theory. Proc. Natl. Acad..Sci USA, 95:11578-11583. 1998. http://www.pubmedcentral.nih.gov/

Rice, W.G.; Huang, M.; McDonnell, N.; Summers, M.F.; Turpin, J.A. , pp. A55

Targeting the HIV-1 Nucleocapsid Protein by Azodicarbonamide ( ADA), Cystamine, and Dithiane Compounds Antiviral Research, Vol: 34, Issue: 2, April 1997 http://www1.elsevier.com/

Garber ME, Wei P, Kewal Ramani VN, Mayall TP, Herrmann CH, Rice AP, Littman DR, Jones KA

The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein . Genes Dev. 1998 Nov 15;12(22):3512-27 page 3522 http://www.genesdev.org/

Nancy A. Jewell (2) and Louis M. Mansky (1)

In the beginning: genome recognition, RNA encapsidation and the initiation of complex retrovirus assembly (1) Department of Molecular Virology, Immunology, and Medical Genetics, Center for Retrovirus Research, and Comprehensive Cancer Center, Ohio State University Medical Center, Journal of General Virology (2000), 81 , 1889­1899. 2078 Graves Hall, 333 West 10th Ave, Columbus, OH 43210, USA(2)Molecular, Cellular, and Developmental Biology Graduate Program, Ohio State University, USA http://vir.sgmjournals.org/

Goebel FRANK-D, et al.

Phase I/II dose escalation and randomized withdrawal study with add-on Azodicarbonamide in patients failing on current antiretroviral therapy. AIDS. 2001 Jan 5; 15(1):33-45. http://www.ncbi.nlm.nih.gov/

EDITORIALS Scott A. Foster, William C. Phelps

Zn 2+ Fingers and Cervical Cancer Journal of the National Cancer Institute, Vol. 91, No. 14, 1180-1181, July 21, 1999 http://jncicancerspectrum.oupjournals.org/

Walter Beerheide, Hans-Ulrich Bernard, Yee-Joo Tan, Arasu Ganesan, William G.Rice, Anthony E. Ting

Potential Drugs Against Cervical Cancer: Zinc-Ejecting Inhibitors of the Human Papillomavirus Type 16 E6 Oncoprotein Journal of the National Cancer Institute, Vol. 91, No. 14, July 21, 1999 pp 1211-1220 http://jncicancerspectrum.oupjournals.org/

Tassignon J, Ismaili J, Le Moine A,Van Laethem F, Leo,Vandevelde M, Goldman M.

Azodicarbonamide inhibits T-cell responses in vitro and in vivo. Nat Med. 1999 Aug;5 (8):947-50. http://www.ncbi.nlm.nih.gov/

Hsu M, Wainberg MA

Interactions between human immunodeficiency virus type 1 reverse transcriptase, tRNA primer, and nucleocapsid protein during reverse transcription. J Hum Virol 2000 Jan-Feb;3(1):16-26 http://www.ncbi.nlm.nih.gov/

Teresa A. Bennett, Bruce S. Edwards,Larry A. Sklar, and Snezna Rogelj

Sulfhydryl Regulation of L-Selectin Shedding: Phenylarsine Oxide Promotes Activation-Independent L-Selectin Shedding from Leukocytes1. The Journal of Immunology, 2000, 164: 4120–4129. http://www.jimmunol.org/

Tassignon J, Vandevelde M, Goldman M.

Azodicarbonamide as a new T cell immunosuppressant: synergy with cyclosporin A. Clin Immunol. 2001 Jul;100(1):24-30. http://www.ncbi.nlm.nih.gov/

Christine Fagny, Michel Vandevelde, Michal Svoboda and Patrick Robberecht Ribonucleotide

reductase and thymidine phosphorylation: two potential targets of Azodicarbonamide Biochemical Pharmacology, Volume 64, Issue 3, 1 August 2002, Pages 451-456 http://www.ncbi.nlm.nih.gov/

Topol I.A. Nemukhin A.V. Dobrogorskaya Ya.I. Burt S.K

Interactions of  Azodicarbonamide ( ADA) species with the model zinc finger site: Theoretical support of the zinc finger domain destruction in the HIV-1 nucleocapsid protein (NCp7) by ADA J.Phys.Chem.B, 2001, V.105, P.11341-11350. http://lcc.chem.msu.ru/anem/

Garcia CC, Candura NA Damonte EB.

Differential inhibitory action of two azoic compounds against arenaviruses. Int J Antimicrob Agents. 2003 Apr;21(4):319-24 http://www.ncbi.nlm.nih.gov/

De Clercq E

Highlights in the development of new antiviral agents. Mini Rev Med Chem. 2002 Apr;2(2):163-75. http://www.ncbi.nlm.nih.gov/

 

 

 
 
 
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