Structure-activity relationships for insect hypertrehalosemic hormone: The importance of side chains and termini

Structure–activity relationship of adipokinetic hormone analogs in the striped hawk moth, Hippotion eson

“…It has been argued previously that the aromatic positions in AKHs, Phe at position 4 and Trp at position 8, are non-negotiable for receptor binding [5,9,17,37]. Here, we tested an analog with Ala at position 8 and scored no significant hyperlipemic activity (Table 2), which confirms the current hypothesis that the two aromatics interact with each other once the molecule has formed its preferred conformation which includes a ␤-bend between residues 5 and 8 [7,26,37,45].…”

“…A far more drastic effect was recorded in L. migratoria when the Thr 10 and the Gly 9 of Locmi-AKH-I was swopped to make a Thr 9 , Gly 10 analog: AKH activity was reduced to 3% [37]. In B. discoidalis, on the other hand, replacements to the 10th amino acid of its hypertrehalosemic decapeptide did not much change the in vivo biological response [9]. In fact, a survey of naturally occurring decapeptide AKHs show that there is quite a diverse possibility of amino acids at position 10, whereas some other positions show relatively little variation (2: Leu, Ile, Val, Phe; 3: Thr, Asn, 4: Phe, Tyr; 5: Thr, Ser; 8: Trp; 9: Gly) (see [15]).…”

“…Previous work had mostly also reported lower activity when the pGlu was replaced by other blocked amino acids [9,17,29,41,42]. In fact, a severe loss of binding was recorded in in vitro receptor binding assays with an N-terminal acetylated-Ala analog of the fruit fly AKH [5], which also points to a change in accessibility of the ligand to the expressed receptor.…”

“…In such structure-activity bioassays, naturally occurring peptides, or systematically altered analogs were injected into the adult test insect to gather information on dose-response, time-course of the biological response and/or ligand efficacy, for example in vivo assays measuring hyperlipemia in the locust species Locusta migratoria and Schistocerca gregaria [12,14,24,25,30,34,37] or in the sphingid moth M. sexta [10], or measuring hypertrehalosemia in the cockroach species Periplaneta americana [11,13,17] and Blaberus discoidalis [9,26]. There are variations of bioassays where the activity of the enzyme glycogen phosphorylase has been measured in larvae of M. sexta [41], and an in vitro assay was used to monitor the uptake of acetate into fat cells of L. migratoria [29].…”

Insect peptide hormones, an overview of the present literature

“…To preserve the hypertrehalosemic properties among the Bld-HrTH analogs (50) it was necessary to maintain the native Glp', Phe4, and Trp' residues in the peptide molecule. migratoria.…”