ABSTRACT
The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.
Subject(s)
Oligopeptides/chemistry , Circular Dichroism , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Oligopeptides/chemical synthesis , Protein Structure, Secondary , StereoisomerismABSTRACT
The molecular structures of 3'-azido-2',3'-dideoxyribosylthymine 5'-triphosphate (AZTTP), 2',3'-dideoxyribosylinosine 5'-triphosphate (ddlTP), 3'-azido-2',3'-dideoxyribosylthymine 5'-monophosphate (AZTMP) and 2',3'-dideoxyribosyladenine 5'-monophosphate (ddAMP) have been studied by NMR to understand their anti-HIV activity. For ddAMP and ddITP, conformations are almost identical with their nucleoside analogues with sugar ring pucker equilibriating between C3'-endo (approximately 75%) and C2'-endo (approximately 25%). AZTMP and AZTTP on the other hand show significant variations in the conformational behaviour compared with 3'-azido-2',3'-dideoxyribosylthymine (AZT). The sugar rings for these nucleotides have a much larger population of C2'-endo (approximately 75%) conformers, like those observed for natural 2'-deoxynucleosides and nucleotides. The major conformers around C5'-O5', C4'-C5' and the glycosidic bonds are the beta 1, gamma + and anti, respectively.
Subject(s)
Antiviral Agents/chemistry , HIV/drug effects , Inosine Triphosphate/analogs & derivatives , Thymine Nucleotides/chemistry , Zidovudine/analogs & derivatives , Antiviral Agents/pharmacology , Dideoxynucleotides , Humans , Inosine Triphosphate/chemistry , Inosine Triphosphate/pharmacology , Magnetic Resonance Spectroscopy/methods , Models, Theoretical , Molecular Conformation , Molecular Structure , Thymine Nucleotides/pharmacology , Zidovudine/chemistry , Zidovudine/pharmacologyABSTRACT
The structure of cyclic antagonists of luteinizing hormone-releasing hormone (LHRH), Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-c(Asp5-D-Arg6-Leu7- Lys8)-Pro9- D-Ala10-NH2 (I), Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-c(Glu5-D-Arg6-Leu7- Lys8)-Pro9-D-Ala10-NH2 (II) and their linear analogues, Ac-D-Phe(p-Cl)1-D- Phe(p-Cl)2-D-Trp3-Ser4-Asp5-D-Arg6-Leu7-Lys8-Pro9-D-++ +Ala10-NH2 (III) and Ac-D-Phe(p-Cl)1-D-Phe(p-Cl)2-D-Trp3-Ser4-Glu5-D-Arg6-Leu7-++ +Lys8-Pro9-D-Ala10-NH2 (IV), have been studied by NMR spectroscopy. The cyclic peptides I and II are more potent antagonists than the corresponding linear peptides in an in vivo assay. All the peptides show propensity of an unusual type II' beta-turn involving residues 3-6. Cyclic analogues also show some additional structure around residues 7 and 8 which is absent in the linear peptides. This additional structure in the cyclic peptides may be due to a minor conformation with a beta-turn between residues 5 and 8.
Subject(s)
Gonadotropin-Releasing Hormone/antagonists & inhibitors , Hormone Antagonists/chemistry , Peptides, Cyclic/chemistry , Peptides/chemistry , Amino Acid Sequence , Animals , Female , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/metabolism , Hormone Antagonists/pharmacology , In Vitro Techniques , Luteinizing Hormone/metabolism , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Ovulation/drug effects , Peptides/pharmacology , Peptides, Cyclic/pharmacology , Pituitary Gland/drug effects , Pituitary Gland/metabolism , Protein Conformation , Protein Structure, Secondary , RatsABSTRACT
The sugar ring conformations of 2',3'-dideoxyribosyladenine (ddA), 2',3'-dideoxyribosylcytosine (ddC), 2',3'-dideoxyribosylguanine (ddG), 2',3'-dideoxyribosylhypoxanthine (ddI), 3'-azido-2',3'-dideoxyribosylthymine (AZT), 3'-azido-2',3'-dideoxyribosyluracil (AZU) and 3'-fluoro-2',3'-dideoxyribosylthymine (FddT) have been investigated by 1H NMR spectroscopy. While the sugar ring in FddT exists almost totally in C2'-endo geometry, other nucleosides show equilibrium between sugar puckers of C3'-endo family (N-type) and C2'-endo family (S-type). For unsubstituted dideoxynucleosides C3'-endo conformer is favoured (congruent to 75%), whereas for AZT and AZU both the conformers have almost equal populations. Unlike X-ray diffraction studies, the NMR results do not support the suggestion that C3'-exo sugar puckers are desirable for the anti-HIV activity of these nucleosides.
Subject(s)
Antiviral Agents , Dideoxynucleosides/chemistry , HIV/drug effects , Dideoxynucleosides/pharmacology , Hydrogen , Magnetic Resonance Spectroscopy/methods , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
1H and 13C NMR study of 3'-azido-2',3'-dideoxyribosylthymine (AZT), an inhibitor of HIV (human immunodeficiency virus) replication, has been undertaken. Modified Karplus relations have been used to obtain the molecular structure from the indirect coupling constants. NMR results are consistent with an anti glycosyl angle, a sugar pucker with equilibrium between C2'-endo and C3'-endo geometries and a predominantly g+ conformation about C4'-C5' bond. These results are in variance with those obtained in the solid state by X-ray diffraction studies.
