An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata

Abstract

Background Kahalalide F (KF) and its isomer iso-kahalalide F (isoKF), both of which can be isolated from the mollusk Elysia rufescens and its diet alga Bryopsis pennata, are potent cytotoxic agents that have advanced through five clinical trials. Due to a short half-life, narrow spectrum of activity, and a modest response in patients, further efforts to modify the molecule are required to address its limitations. In addition, due to the high cost in producing KF analogues using solid phase peptide synthesis (SPPS), a degradation and reconstruction approach was employed using natural KF from a seasonal algal bloom to generate KF analogues. Methods N-protected KF was carefully hydrolyzed at the amide linkage between l-Thr12 and dVal13 using dilute HCl. The synthesis of the C-terminal fragment began with the formation of hexanoic succinimide ester, followed by a reaction with dipeptides. The final coupling reaction was performed between the semisynthesized Fmoc-KF hydrolysis product and the C-terminal fragment, followed by the deprotection of the Fmoc group. Results Six KF analogues with an addition of an amino acid residue on the N-terminal chain, d-Val14-isoKF (2), Val13-Val14-isoKF (3), d-Leu14-isoKF (4), d-Pro14-isoKF (5), d-Phe14-isoKF (6), and 3,4-2F-d-Phe14-isoKF (7) were prepared using semisynthesis at the exposed N-terminal chain. General Significance B. pennata blooms are capable of producing KF in good yields. The semisynthesis from the natural product produced N-terminal modifications for the construction of inexpensive semisynthetic KF libraries. This approach is economical, efficient and amendable to large-scale production while eliminated a nuisance algal bloom.

Marine natural products

“…507 An efficient and cost-effective method for the production of kahalalide congeners for advanced biological testing is based on the selective hydrolysis of N-protected kahalalide F isolated from nuisance blooms of Bryopsis pennata. 508 By combining virtual-and structure-based ligand screening approaches, a database of >100 caulerpin analogues was efficiently evaluated in silico for potential inhibitory activity against monoamine oxidase B, 509 while astaxanthin and other algal carotenoids have been the focus of many studies and reviews. [510][511][512][513][514][515][516][517][518]…”

Diverse Applications of Marine Macroalgae

“…One example is the peptide kahalalide F and its isomer, iso-kahalalide F, extracted from a green macroalga, Bryopsis pennata, which present cytotoxic effects and were used in anticancer clinical trials. Despite its great potential, this molecule is under modification tests to improve its water solubility, stability, and effectiveness [70].…”

“…ulvans). Their value lies on their bioactivities, namely their antibacterial, antiviral activity, antitumoral, and immunomodulatory potential [8,70,72,73].…”

Bioactive Peptides from Marine Molluscs – A Review

“…Side effects reported were fatigue, headache, vomiting, and pruritus limited to the hands [6]. Hematological toxicities have not been observed on treatment with Kahalalide F thus showing its suitability for trials in combination with other anticancer agents [6,49]. Unfortunately, due to a lack of efficacy, Kahalalide F was removed from phase II clinical trials in spite of the fact that a few patients achieved a positive response [32].…”