Anti-HIV agents that selectively target retroviral nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins

Journal of Medicinal Chemistry
M HuangW G Rice

Abstract

Agents that target the two highly conserved Zn fingers of the human immunodeficiency virus (HIV) nucleocapsid p7 (NCp7) protein are under development as antivirals. These agents covalently modify Zn-coordinating cysteine thiolates of the fingers, causing Zn ejection, loss of native protein structure and nucleic acid binding capacity, and disruption of virus replication. Concentrations of three antiviral agents that promoted in vitro Zn ejection from NCp7 and inhibited HIV replication did not impact the functions of cellular Zn finger proteins, including poly(ADP-ribose) polymerase and the Sp1 and GATA-1 transcription factors, nor did the compounds inhibit HeLa nuclear extract mediated transcription. Selectivity of interactions of these agents with NCp7 was supported by molecular modeling analysis which (1) identified a common saddle-shaped nucleophilic region on the surfaces of both NCp7 Zn fingers, (2) indicated a strong correspondence between computationally docked positions for the agents tested and overlap of frontier orbitals within the nucleophilic loci of the NCp7 Zn fingers, and (3) revealed selective steric exclusion of the agents from the core of the GATA-1 Zn finger. Further modeling analysis suggests that the thiola...Continue Reading

References

Aug 29, 1979·Biochimica Et Biophysica Acta·N A BergerS J Berger
Nov 11, 1992·Proceedings of the National Academy of Sciences of the United States of America·M R ChanceT L South
Mar 26, 1992·Nature·M S Satoh, T Lindahl
Jan 1, 1995·Advances in Pharmacology·W G Rice, J P Bader
Jun 30, 1995·Annals of the New York Academy of Sciences·A Klug
Sep 1, 1995·Protein Science : a Publication of the Protein Society·A WallqvistD G Covell
Feb 6, 1996·Proceedings of the National Academy of Sciences of the United States of America·P J TumminoD Hupe
May 1, 1996·AIDS Research and Human Retroviruses·M VandeveldeJ P Tassignon
Mar 1, 1997·Nucleic Acids Research·J A BerglundM Rosbash
Jul 4, 1997·Science·J Cohen

❮ Previous
Next ❯

Citations

Oct 9, 2002·Medicinal Research Reviews·Erik De Clercq
Sep 5, 2002·Biochemical and Biophysical Research Communications·Andrew G StephenRobert J Fisher
Jul 31, 2002·Biochemical Pharmacology·Christine FagnyPatrick Robberecht
May 12, 2001·Il Farmaco·E De Clercq
Aug 24, 2012·Biochemistry·Mikaela D Stewart, Tatyana I Igumenova
Jun 6, 2009·Antioxidants & Redox Signaling·Georg T Wondrak
Jul 25, 2000·Journal of Virology·R J MillerN Sarver
Nov 26, 2009·Molecular Endocrinology·Terry W MooreJohn A Katzenellenbogen
Nov 12, 2002·Environmental Health Perspectives·Angela CasiniClaudiu T Supuran
Jul 19, 2011·Journal of Molecular Biology·Leslie J Parent, Nicole Gudleski
Mar 2, 2016·Journal of the American Chemical Society·Yu-Ming LeeCarmay Lim
Oct 13, 2006·Analytical Biochemistry·Margareta CruceanuMark C Williams
Jun 21, 2001·Clinical Immunology : the Official Journal of the Clinical Immunology Society·J TassignonM Goldman
Jul 16, 2014·Virus Research·Divita Garg, Bruce E Torbett
Jul 20, 2000·Antiviral Chemistry & Chemotherapy·C C GarcíaE B Damonte
Feb 16, 2016·Journal of Inorganic Biochemistry·Patricia B Lutz, Craig A Bayse
Oct 16, 2004·Expert Review of Anti-infective Therapy·Jim A Turpin
May 14, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Zhifeng DuNicholas Farrell
Sep 5, 2002·Proteins·Thomas Simonson, Nicolas Calimet
Feb 26, 2013·Chemistry : a European Journal·Aurélie JacquesOlivier Sénèque
Apr 26, 2008·Protein Science : a Publication of the Protein Society·Richa Jaiswal, Dulal Panda
Jul 30, 1999·Nature Medicine·J TassignonM Goldman
Jul 17, 2020·British Journal of Pharmacology·Urszula DoboszewskaKatarzyna Młyniec
Dec 3, 2016·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Saliu A AmolegbeJoshua A Obaleye
Dec 4, 2019·Physical Chemistry Chemical Physics : PCCP·Prasanta BandyopadhyayMd Motin Seikh

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.