Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains

T20 (generic name: Enfuvirtide, brand name: Fuzeon) is the only FDA-approved HIV fusion inhibitor that is being used for treatment of HIV/AIDS patients who have failed to respond to current antiretroviral drugs. However, it rapidly induces drug resistance in vitro and in vivo. On the basis of the structural and functional information of anti-HIV peptides from a previous study, we designed an HIV fusion inhibitor named CP32M, a 32-mer synthetic peptide that is highly effective in inhibiting infection by a wide range of primary HIV-1 isolates from multiple genotypes with R5- or dual-tropic (R5X4) phenotype, including a group O virus (BCF02) that is resistant to T20 and C34 (another anti-HIV peptide). Strikingly, CP32M is exceptionally potent (at low picomolar level) against infection by a panel of HIV-1 mutants highly resistant to T20 and C34. These findings suggest that CP32M can be further developed as an antiviral therapeutic against multidrug resistant HIV-1.

[1]  Yonghong Xiao,et al.  Design and Evaluation of Sifuvirtide, a Novel HIV-1 Fusion Inhibitor* , 2008, Journal of Biological Chemistry.

[2]  B. Berkhout,et al.  Selection of T1249-Resistant Human Immunodeficiency Virus Type 1 Variants , 2008, Journal of Virology.

[3]  Hong Lu,et al.  Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors , 2008, Journal of Virology.

[4]  A. Debnath,et al.  Conserved Residue Lys574 in the Cavity of HIV-1 Gp41 Coiled-coil Domain Is Critical for Six-helix Bundle Stability and Virus Entry* , 2007, Journal of Biological Chemistry.

[5]  F. Kirchhoff,et al.  Human Immunodeficiency Virus Type 1 Variants Resistant to First- and Second-Version Fusion Inhibitors and Cytopathic in Ex Vivo Human Lymphoid Tissue , 2007, Journal of Virology.

[6]  D. Chang,et al.  Biophysical evidence of two docking sites of the carboxyl heptad repeat region within the amino heptad repeat region of gp41 of human immunodeficiency virus type 1. , 2007, Antiviral research.

[7]  K. Taylor,et al.  AIDS virus envelope spike structure. , 2007, Current opinion in structural biology.

[8]  Shibo Jiang,et al.  HIV gp41 C-terminal Heptad Repeat Contains Multifunctional Domains , 2007, Journal of Biological Chemistry.

[9]  Shibo Jiang,et al.  HIV entry inhibitors targeting gp41: from polypeptides to small-molecule compounds. , 2007, Current pharmaceutical design.

[10]  J. Erickson,et al.  Impact of Human Immunodeficiency Virus Type 1 gp41 Amino Acid Substitutions Selected during Enfuvirtide Treatment on gp41 Binding and Antiviral Potency of Enfuvirtide In Vitro , 2005, Journal of Virology.

[11]  E. Poveda,et al.  Enfuvirtide, the first fusion inhibitor to treat HIV infection. , 2005, AIDS reviews.

[12]  Shibo Jiang,et al.  Different from the HIV Fusion Inhibitor C34, the Anti-HIV Drug Fuzeon (T-20) Inhibits HIV-1 Entry by Targeting Multiple Sites in gp41 and gp120* , 2005, Journal of Biological Chemistry.

[13]  A. Debnath,et al.  N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion , 2004, Antimicrobial Agents and Chemotherapy.

[14]  F. Castellino,et al.  A single amino acid replacement results in the Ca2+-induced self-assembly of a helical conantokin-based peptide. , 2004, Biochemistry.

[15]  M. Greenberg,et al.  Resistance to enfuvirtide, the first HIV fusion inhibitor. , 2004, The Journal of antimicrobial chemotherapy.

[16]  F. Castellino,et al.  Binding and orientation of conantokins in PL vesicles and aligned PL multilayers. , 2003, Biochemistry.

[17]  C. Weiss.  HIV-1 gp41: mediator of fusion and target for inhibition. , 2003, AIDS reviews.

[18]  Shibo Jiang,et al.  Determination of the HIV-1 gp41 fusogenic core conformation modeled by synthetic peptides: applicable for identification of HIV-1 fusion inhibitors , 2003, Peptides.

[19]  B. Clotet,et al.  HIV-1 resistance to the gp41-dependent fusion inhibitor C-34. , 2003, Antiviral research.

[20]  Shibo Jiang,et al.  Enhancement of Human Immunodeficiency Virus Type 1 lnCection by Antisera to Peptides from the Envelope Glycoproteins gp120/gp41 , 2003 .

[21]  Min Lu,et al.  Genetic Evidence that Interhelical Packing Interactions in the gp41 Core Are Critical for Transition of the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein to the Fusion-Active State , 2002, Journal of Virology.

[22]  J. Kappes,et al.  Emergence of Resistant Human Immunodeficiency Virus Type 1 in Patients Receiving Fusion Inhibitor (T-20) Monotherapy , 2002, Antimicrobial Agents and Chemotherapy.

[23]  J. Hoxie,et al.  Mutations That Destabilize the gp41 Core Are Determinants for Stabilizing the Simian Immunodeficiency Virus-CPmac Envelope Glycoprotein Complex* , 2002, The Journal of Biological Chemistry.

[24]  Min Lu,et al.  Structural and Functional Analysis of Interhelical Interactions in the Human Immunodeficiency Virus Type 1 gp41 Envelope Glycoprotein by Alanine-Scanning Mutagenesis , 2001, Journal of Virology.

[25]  J. Liu,et al.  Helical interactions in the HIV-1 gp41 core reveal structural basis for the inhibitory activity of gp41 peptides. , 1999, Biochemistry.

[26]  D. Chang,et al.  Biophysical Characterization of the Structure of the Amino-terminal Region of gp41 of HIV-1 , 1999, The Journal of Biological Chemistry.

[27]  P S Kim,et al.  Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. S. Kim,et al.  HIV Entry and Its Inhibition , 1998, Cell.

[29]  T. Matthews,et al.  Determinants of Human Immunodeficiency Virus Type 1 Resistance to gp41-Derived Inhibitory Peptides , 1998, Journal of Virology.

[30]  Stephen C. Blacklow,et al.  A trimeric structural domain of the HIV-1 transmembrane glycoprotein , 1995, Nature Structural Biology.

[31]  T. Matthews,et al.  Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Matthews,et al.  A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. , 1993, AIDS research and human retroviruses.

[33]  Shibo Jiang,et al.  HIV-1 inhibition by a peptide , 1993, Nature.

[34]  T. Oas,et al.  A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Y H Chen,et al.  Determination of the helix and beta form of proteins in aqueous solution by circular dichroism. , 1974, Biochemistry.