Synthetic CD4 exocyclics inhibit binding of human immunodeficiency virus type 1 envelope to CD4 and virus replication in T lymphocytes.
CD4 functions as a major T-cell surface receptor for human immunodeficiency virus by binding the human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 with relatively high affinity. We have developed constrained aromatically modified analogs of the secondary structures of the first domain of CD4 in order to analyze surfaces involved in binding of gp120. Complementarity determining-like regions (CDRs) of the D1 domain of CD4 were reproduced as synthetic aromatically modified exocyclic (AMEs) forms. The exocyclic CDR3.AME(82-89), derived from the CDR3 (residues 82-89) region of CD4 D1 domain, specifically inhibited binding of recombinant gp120 to both recombinant soluble CD4, and CD4+ Jurkat cells, and blocked syncytium formation and virus particle production caused by HIV-1 infection. We have previously shown that the CDR3.AME analog binds to the CD4 CDR3 region and creates a disabled CD4 heterodimer. We propose that the AME prevents the formation of an essential homodimeric surface needed for efficient HIV binding. Additionally the disabled CD4 receptor may be less able to signal the cell to allow HIV replication and HIV infection. Such compounds may represent a new receptor specific approach to modulate biological functions.
Zhang
X
X
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.
Gaubin
M
M
Briant
L
L
Srikantan
V
V
Murali
R
R
Saragovi
U
U
Weiner
D
D
Devaux
C
C
Autiero
M
M
Piatier-Tonneau
D
D
Greene
M I
MI
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000502:physiology; D015704:CD4 Antigens / Q000737:chemistry* / Q000502:physiology; D015195:Drug Design; D015726:Giant Cells / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology*; D014779:Virus Replication / Q000187:drug effects*
D015703:Antigens, CD; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017260:Receptor-CD3 Complex, Antigen, T-Cell