Human immunodeficiency virus type 1 integrase (HIV‐1 IN) which catalyzes viral DNA integration into the host genome of infected cells represents an attractive target for AIDS therapy. We have previously demonstrated the ability of the IN‐(147−175)‐peptide derived from the catalytic core domain of HIV‐1 IN to inhibit the enzyme activity in vitro. IN‐(147−175)‐peptide contains four heptad repeats and displays a high propensity for coiled‐coil formation while its [P159]IN‐(147−175)‐peptide analog (Lys159←Pro in the protein, Lys13←Pro in the peptide) is unable to form a stable coiled‐coil and is devoid of inhibitory activity [Sourgen, F., Maroun, R. G., Frère, V., Bouziane, M., Auclair, C., Troalen, F. & Fermandjian, S. (1996) Eur. J. Biochem. 240, 765−773]. Now, we report results from an NMR study on IN‐(147−175)‐peptide and [P159]IN‐(147−175)‐peptide as well as on an optimized [E156, A163, A167]IN‐(147−175)‐peptide that is a better inhibitor of IN than IN‐(147−175)‐peptide. While in aqueous solution, IN‐(147−175)‐peptide and [P159]IN‐(147−175)‐peptide display only nascent helical features, [E156, A163, A167]IN‐(147−175)‐peptide exhibits 20 % of helical content. In 20 % trifluoroethanol/80 % H2O, the helix content is the highest for [E156, A163, A167]IN‐(147−175)‐peptide (≈70 %) and the lowest for [P159]IN‐(147−175)‐peptide (≈40 %), due to a local helix break caused by the Pro residue. The NHs of residues in the two central helical heptads (a−g) of IN‐(147−175)‐peptide and [E156, A163, A167]IN‐(147−175)‐peptide display a regular periodic variation of their temperature coefficients in 20 % trifluoroethanol. The b, c and f residues on the hydrophilic face of the amphipathic helix show high coefficients reflecting hydrogen bonded NHs, while the a and d residues on the hydrophobic face exhibit low coefficients, near random‐coil values. The particular arrangement of the hydrophobic side‐chains of a and d residues at the coiled‐coil interface reduces the access of trifluoroethanol molecules to their amide groups. The inability of trifluoroethanol molecules to create interactions with the amide C=O groups, these being required to strengthen the intrahelical C=O H‐N hydrogen bonds, is the main cause for observation of heptadic a and d residues with low NH temperature coefficients. Such effects concern mostly the two central helical heptads of IN‐(147−175)‐peptide and [E156, A163, A167]IN‐(147−175)‐peptide implying that these ones are engaged in stable parallel coiled coils. Our results provide a link between the propensity of peptides for helix formation, their coiled‐coil properties and their efficiency to inhibit IN.