title: Site-specific Substitutions Eliminate Aggregation Properties of Hemopressin.
abstract: Hemopressin is a naturally occurring and therapeutically relevant peptide with applications in hypertension, pain, addiction, and obesity. We had previously demonstrated that hemopressin converts into amyloid-like fibrils under aqueous conditions. However, the amino acid residues that modulate the aggregation propensity of hemopressin were not identified. In this study, we designed and synthesized 25 different analogs of hemopressin and analyzed their aggregation properties using the principle of dynamic light scattering. As a result, we were able to identify four conservative changes in the peptide sequence (Val(2) →DVal(2), Asn(3) →Gln(3) Leu(7) →Npg(7) and C-OH→C-NH2) that minimize aggregation propensity of hemopressin. The results indicate that hemopressin aggregation is cooperative in nature and involves contribution from multiple amino acids within the peptide chain. The analogs and the corresponding aggregation propensity data reported in this study would be useful for researchers investigating therapeutic properties of hemopressin, which have been hampered due to the tendency of hemopressin to aggregate in aqueous solutions.
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Harrisonburg, VA, 22801, USA.
authors.forename: Benben
authors.initials: B
authors.lastname: Song
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Harrisonburg, VA, 22801, USA.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Kibler
authors.affiliation: Preclinical and Development, Biosciences Division, SRI International, Menlo Park, CA, 94025, USA.
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Endsley
authors.affiliation: Center for Cancer and Metabolism, Biosciences Division, SRI International, Harrisonburg, VA, 22801, USA.
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Nayak
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Harrisonburg, VA, 22801, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Galande
authors.affiliation: Center for Chemical Biology, Biosciences Division, SRI International, Harrisonburg, VA, 22801, USA.
authors.forename: Kalyani
authors.initials: K
authors.lastname: Jambunathan
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015195:Drug Design; D000067493:Dynamic Light Scattering; D006454:Hemoglobins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057446:Hydrodynamics; D051379:Mice; D008969:Molecular Sequence Data; D010316:Particle Size; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D066329:Protein Aggregates
chemical_list: D006454:Hemoglobins; D010446:Peptide Fragments; D066329:Protein Aggregates; C473218:hemopressin
keywords: amyloid-like fibrils; bioactive peptides; dynamic light scattering; hemopressin; peptide aggregation