COMPARISON OF THE SOLUTION CONFORMATIONS OF A HUMAN-IMMUNODEFICIENCY-VIRUS PEPTIDOMIMETIC AND ITS RETRO-INVERSO ISOMER USING H-1-NMR SPECTROSCOPY

The solution conformations of the all L-alpha-peptide 1 and the corres ponding retro-all D-alpha-peptide 2, two 20-meric peptides which gener ate antibodies that cross-react with the gp120 envelop protein of huma n immunodeficiency virus-1 (HIV-1), have been investigated by high-fie ld 1(H) NMR spectroscopy. Complete sequential and interresidue interac tion assignments were made from the 2D NMR spectra acquired at 500 MHz and 600 MHz in 40% deuterotrifluoroethanol (d(3)-TFE)/H2O at pH 2.3, and in 300 mM sodium dodecyl sulphate (SDS) in 100% D2O or 90% H2O/10% D2O at pH 2.6. Based on analysis of the nuclear Overhauser effect (NO E) and amide exchange data, peptide 1 and its retro-inverso isomer 2 i n the polar solvent environment of 40% d(3)-TFE/H2O at pH 2.3 show ver y similar topological features. However, in the relatively non-polar 3 00 mM SDS micellar environment, peptides 1 and 2 exhibit differences i n their solution structures in terms of the amide backbone and side-ch ain orientations. Tn particular, under the SDS micellar condition, pep tide 1 maintains much of the secondary structure observed for this 20- mer peptide in 40% d(3)-TFE/H2O, pH 2.3, whereas peptide 2 adopts a mo re extended structure. These NMR results provide the first confirmatio n that the secondary structure of the all L-a-peptide 1 is maintained in both polar and non-polar environments, whereas the secondary struct ure and topology of the notionally equivalent retro-inverso isomer dep ends more on the solvent conditions. These results with the all L-alph a-peptide 1 and its retro-inverso isomer 2 provide important insight i nto the conformational influences of the C- and N-end group with L-alp ha- and retro-D-alpha-isomer pairs in non-polar environments, and thus have general relevance to the design of bioactive retro-inverso pepti domimetic analogues related to immunogenic or hormonal peptides. (C) M unksgaard 1997.