Leveraging Peptaibol Biosynthetic Promiscuity for Next-Generation Antiplasmodial Therapeutics

Abstract

Malaria remains a worldwide threat, afflicting over 200 million people each year. The emergence of drug resistance against existing therapeutics threatens to destabilize global efforts aimed at controlling Plasmodium spp. parasites, which is expected to leave vast portions of humanity unprotected against the disease. To address this need, systematic testing of a fungal natural product extract library assembled through the University of Oklahoma Citizen Science Soil Collection Program has generated an initial set of bioactive extracts that exhibit potent antiplasmodial activity (EC 50 < 0.30 μg/mL) and low levels of toxicity against human cells (less than 50% reduction in HepG2 growth at 25 μg/mL). Analysis of the two top-performing extracts from Trichoderma sp. and Hypocrea sp. isolates revealed both contained chemically diverse assemblages of putative peptaibol-like compounds that were responsible for their antiplasmodial actions. Purification and structure determination efforts yielded 30 new peptaibols and lipopeptaibols (1−14 and 28−43), along with 22 known metabolites (15−27 and 44−52). While several compounds displayed promising activity profiles, one of the new metabolites, harzianin NPDG I (14), stood out from the others due to its noteworthy potency (EC 50 = 0.10 μM against multi-drugresistant P. falciparum line Dd2) and absence of gross toxicity toward HepG2 at the highest concentrations tested (HepG2 EC 50 > 25 μM, selectivity index > 250). The unique chemodiversity afforded by these fungal isolates serves to unlock new opportunities for translating peptaibols into a bioactive scaffold worthy of further development.

Acremopeptaibols A–F, 16-Residue Peptaibols from the Sponge-Derived Acremonium sp. IMB18-086 Cultivated with Heat-Killed Pseudomonas aeruginosa

“…The 13 C NMR (Table ) and DEPT spectra displayed 79 carbon resonances, including 18 amide carbonyls, 16 α-amino carbons (seven methines, two methylenes, and seven nonprotonated), and 16 methyl carbons. These spectroscopic features suggested that compound 1 belonged to the family of peptaibol natural products containing 16–18 amino acid residues. − …”

Eleven‐Residue Peptaibols Isolated from Trichoderma longibrachiatum Rifai DMG‐3‐1‐1and Their Structure‐Activity Relationship

“…Combined analyses of 1 H-1 H COSY, HMBC, HSQC and TOCSY spectra further revealed the presence of 2 × Val, 2 × Leu, 2 × Pro, 2 × Aib, 1 × Asn, 1 × Ileol and N-Ac-Aib residues (Table 1), which were in accordance with the result of Marfey's analysis (Figure 3). The acetyl group was also assumed to be in one terminal as the cases found in known peptaibols, the HMBC of CO (δ C 170.8, Ac-)/NH-1 (δ H 8.59 s, Aib 1 ) indicated the first Aib 1 residue; subsequent ROESY correlations of NH-1/NH-2 (δ H 8.36 d, Asn 2 ), NH-2/NH-3 (δ H 7.70 d, Val 3 ), NH-3/NH-4 (δ H 7.34 d, Val 4 ), NH-4/NH-5(δ H 7.91 s, Aib 5 ), NH-5/δ-H 2 (δ H 3.64 -3.68 m, 3.39 dt, Pro 6 -δ-H 2 ), α-H (δ H 4.20 t, Pro 6 -α-H)/NH-7 (δ H 7.53 d, Leu 7 ), NH-7/ NH-8 (δ H 7.19 d, Leu 8 ), NH-8/NH-9(δ H 7.52 s, Aib 9 ), NH-9/δ-H 2 (δ H 3.62 -3.64 m, Pro 10 -δ-H 2 ) and α-H (δ H 4.22 -4.28 m, Pro 10 -α-H)/NH-11 (δ H 7.02 d, Ileol 11 ), established the planar structure of 6 as Ac-Aib 1 -Asn 2 -Val 3 -Val 4 -Aib 5 -Pro 6 -Leu 7 -Leu 8 -Aib 9 -Pro 10 -Ileol 11 , which was further confirmed by the MALDI-MS/MS analysis (Fig- ure 2) of 6.…”

“…Peptaibols are a family of linear peptides generally composed of 5-22 amino acid residues, characterized by N-acyl terminus, C-amino alcohol terminus, and a high proportion of nonproteinogenic amino acids such as αaminoisobutyric acid (Aib) or isovaline (Iva). [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] In the past five years, peptaibols have attracted attentions of many natural product researchers for their potential bioactivities including cytotoxicities, [1][2][3][4][6][7][8][9]11,15,16] antibacterial activities, [1,2,11,13] antifungal activities, [9,10,12] anti-plasmodial activities [5] and anti-viral activities, [14] et al Peptaibols have been isolated from several genera of fungus, such as Trichoderma, [2][3][4][8][9][10][12][13][14]…”

“….03(5), orthorhombic, space group P21 2 1 2 (no. 18), a = 33.0849(3) Å, b = 19.2288(2) Å, c = 10.88940(10) Å, V = 6927.65(11) Å3, Z = 4, T = 99.99(10) K, μ(CuKα) = 0.697 mm À 1 , D calc.…”

Exploring Peptaibol’s Profile, Antifungal, and Antitumor Activity of Emericellipsin A of Emericellopsis Species from Soda and Saline Soils

“…Peptaibols, the largest group of peptaibiotics, are a class of linear peptides that have an acylated N terminus group, a C-terminal amino acid, and a high content of α-aminoisobutyric acid (Aib)—approximately 40% of Aib in long peptaibols and from 14 to 56% in short peptaibols [ 7 , 11 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Peptaibols are dominant secondary metabolites of filamentous fungi including the ones exhibiting a mycoparasitic lifestyle [ 22 , 24 , 25 , 29 , 30 ].…”