Qiyan Jia

Short cyclic peptides derived from the C-terminal sequence of α1-antitrypsin exhibit significant anti-HIV-1 activity.

Serpin A1 (α1-AT), the largest subgroup of serpins, presents in human plasma at high concentration and plays important regulatory roles in physiological and pathological processes. Accumulated evidence suggests that α1-AT may play a role in controlling HIV-1 infection. In this study, we designed and synthesized a set of short linear peptides derived from the C-terminal sequence of α1-AT. Since none of them showed significant anti-HIV-1 activity, we proceeded to synthesize four short cyclic peptides having 7 amino acids, and we found that three of them exhibited significant anti-HIV-1 activity. One of these cyclic peptides, designated CPM, inhibited HIV-1 entry and infection at low μM level, indicating that these short cyclic peptides could serve as leads for the development of novel anti-HIV-1 therapeutics.

Heteromeric Assembled Polypeptidic Artificial Hydrolases with a Six‐Helical Bundle Scaffold

Enzyme efficiency results from the cooperation of functional groups in the catalytic site. In order to mimic a natural enzyme, a definite 3D scaffold must be carefully designed so that the functional groups can work cooperatively. During the HIV‐1 fusion process, the gp41 N‐ and C‐terminal heptad repeat regions form a coiled‐coil six‐helical bundle (6HB) that brings the viral and target cell membranes into close proximity for fusion. We used 6HB as the molecular model for a novel scaffold for the design of an artificial enzyme, in which the modified C34 and N36 peptides formed a unique 6HB structure through specific molecular recognition, and the position and orientation of the side‐chain groups on this scaffold were predictable. The histidine modified 6HB C34H13/20/N36H15/22 showed enzyme‐like hydrolytic activity towards p‐nitrophenyl acetate (PNPA; kcat/KM=3.66 M−1 s−1) through the cooperation of several inter‐ or intrahelical imidazole groups. Since the catalytic activity of 6HB depends on the C‐ and N‐peptide assembly, either HIV fusion inhibitors that can compete with the formation of catalytic 6HB or denaturants that can destroy the ordered structure were able to modulate its activity. Further engineering of the solvent‐exposing face with Glu−‐Lys+ salt bridges enhanced the helicity and the stability of 6HB. As a result, the population and stability of cooperative catalytic units increased. In addition, the Glu−‐Lys+‐stabilized 6HB SC35H13/20/N36H15/22 had increased catalytic efficiency (kcat/KM=6.30 M−1 s−1). A unique 6HB system was specifically assembled and provided a scaffold sufficiently stable to mimic the function of enzymes or other biomolecules.