Today, microbial infections are a significant human concern globally. The emergence of infectious diseases and the scarcity of vaccines pose a significant danger to human health; thus, there is an immediate need to develop new antimicrobial agents [30]. Vespa orientalis’s crude venom contains peptides and proteins. The venom has antimicrobial activity against Gram-positive and Gram-negative bacteria at very low concentrations relative to tetracycline (positive control). The inhibition zones were 10.2, 12.6, 22.4, and 22.7 mm for Klebsiella pneumonia, Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, respectively, while MIC values were 128, 64, 64, and 8 μg/mL, respectively. The MIC₅₀ and MIC₉₀ values were 74.4 and 119.2 μg/mL for K. pneumonia, 63.6 and 107 μg/mL for S. aureus, 45.3 and 65.7 μg/mL for E. coli, and 4.3 and 7.0 μg/mL for B. subtilis, respectively [31]. Previous studies have determined that the venom from Parischnogaster, Liostenogaster, Eustenogaster, and Metischnogaster wasps inhibited the development of Gram-positive B. subtilis, Gram-negative E. coli, and Saccharomyces cerevisiae yeast [32]. The peptide mastoparan-c, derived from Vespa crabro venom, triggered antimicrobial action toward resistant strains of S. aureus (Gram-positive) bacteria [26].

Inflammation is an underlying cause of several destructive disorders such as arthritis, cancer, and asthma. Anti-inflammatory medications are currently used to suppress short- and long-term body responses, and thus, it is vital to recognize new molecules with similar properties [33]. Vespa tropica venom effectively reduced oxidative stress and stimulated microglia via lipopolysaccharides (LPS) release. Wasp venom treatment (5 and 10 μg/mL) greatly attenuated LPS induced activation of NF-kB phosphorylation [34]. Bracon hebetor venom (BHV) affected LPS-induced nitric oxide (NO) in RAW 264.7 cells and septic shock in mouse models. BHV strongly mediated LPS-induced inflammation without any cytotoxicity at a concentration of 0.1–0.4 μg/mL [35]. Moreover, Nasonia vitripennis venom contains at least 80 proteins, and it exerts anti-inflammatory impacts via down-regulation of the proinflammatory cytokine IL-1β [27].

Polybia paulista wasp venom concentrations below 0.01–10 μg/mL did not cause cytotoxicity and showed genotoxic and mutagenic potential in HepG2 cells. The genotoxic and mutagenic behavior of P. paulista venom could be explained by the action of phospholipase, mastoparan, and hyaluronidase, leading to cell membrane disruption and genetic material alterations or even DNA mutations [29].

The venom of Polybia occidentalis, a social wasp, has anticoagulant, and fibrinogen-degrading pharmacological properties. Anticoagulation occurs at different stages of the clotting process (intrinsic, extrinsic, and specific pathway). Venom can inhibit platelet aggregation and destroy plasma fibrinogens [28].

The mastoparans are comprised of a class of peptides isolated from Vespula lewisii [38], V. crabro [26], Vespula vulgaris [4], and Polistes jadwigae [39]. Mastoparans are characterized by their antitumor activity against melanoma cells (B16F10-Nex2) [38].

Anoplin (ANP) is the smallest antimicrobial, naturally occurring peptide isolated from the solitary spider wasp Anoplius samariensis (Hymenoptera: Pompillidae) and contains ten amino acids (Table 1), making it an ideal research template [55]. The peptide causes mast cell degranulation and has antimicrobial activity [55]. The presence of four-polar residues makes ANP water-soluble. Its interaction with amphipathic environments, such as trifluoroacetic acid (TFE)/water mixtures, or with anisotropic media, such as sodium dodecyl sulfate (SDS) micelles or anionic vesicles, induces α-helical conformations and amphiphilic properties as indicated by the circular dichroism (CD) spectra [55]. ANP inhibited the proliferation of murine erythroleukemia (MEL) cells in a time- and dose-dependent manner. The IC₅₀ values were 161.49, 121.03, and 114.88 μM at 24, 48, and 72 h, respectively. Disrupting the cell membrane integrity was the primary mechanism behind anoplin’s cytotoxicity [56].

Synthetic ANP peptides have a broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria. ANP antimicrobial activity is susceptible to salt. Gram-negative bacteria were entirely immune to ANP in high-salt media (150 mM NaCl); however, Gram-positive bacteria’s efficacy was greatly diminished [55]. Equally interesting, it stimulates rat peritoneal mast cell degranulation, and ANP’s hemolytic activity was relatively low or virtually inactive on human erythrocytes [55].

ANP’s activity is highly sensitive to minor changes of the primary structure, such as single amino acid mutations in certain positions. For example, 37 anoplin analogs have been synthesized by replacing single and multiple residues leading to a change in amphipathicity and charge. Accordingly, the effects against S. aureus and E. coli varied considerably depending on the hydrophobicity and position of the various replaced amines. Residue replacement at positions 5, and 8 with phenylalanine or tryptophan caused by an increase in antibacterial, and hemolytic activity owed to the role of these aromatic residues in the membrane anchoring. Lysine placement in position 8 improved peptide selectivity for prokaryotic cells due to the higher charge [57], whereas C-and N-terminal truncation and C-terminus deamidation drastically decreased peptide antibacterial properties [58]. Antimicrobial activities were measured against E. coli and B. subtilis for all three derivatives of ANP (ANP-NH₂, D-ANP-NH₂, and ANP-OH). Both amidated ANP derivatives display 50 μg/mL, MIC values for B. subtilis, and 100 μg/mL for E. coli. Alternatively, the deamidated form showed significantly lower bactericidal activity with MIC values of 200 μg/mL. The LD₅₀ values for both amidated ANP forms were identical and approximately 10- to 30-fold lower than those of ANP-OH. ANP loses its biological activity after deamidation. Both amidated and carboxylated forms have secondary structures similar to those of the lytic ANP [59]. The natural cationic ANP was modified by substituting residues Gly1 for Lys or Arg, Arg⁵ for Phe, and Thr⁸ for Lys. The antimicrobial properties change dramatically, and high activity against Gram-negative bacterium Zymomonas mobilis at MIC 7 μg/mL was observed, compared to native peptide MIC 200 μg/mL; additionally, it was non-toxic to erythrocytes and resistant to proteolysis [10]. Interestingly, the antimicrobial activities of ANP and analogs ANP-2 (WLLKRWKLL-NH₂), and ANP-4 (KLLKWKKLL-NH₂) were significantly higher than ANP-1 (WLLKRWKKLL-NH₂) and ANP-3 (KLLKWWKKLL-NH₂). The highest antimicrobial activity against B. subtili was shown by ANP-2 and ANP-4 (MIC value: 4 μM) compared to the parent peptide (MIC value: 32 µM). ANP-4 treatment significantly reduced the mortality rate of mice infected with E. coli compared to ANP. ANP-4 is a novel analog of ANP with high antimicrobial activity and enzyme stability that represent it as a successful agent for infections treatment [60].

Decoralin (Dec-NH₂) is a peptide derived from the solitary Eumenine wasp (Oreumenes decoratus) [61] and was synthesized by solid-phase synthesis [62]. Equally important, a natural antimicrobial peptide, Dec-NH₂, was isolated from wasp venom, and its synthetic derivatives were manufactured using peptide design. Dec-NH₂ exhibits potent activity toward cancer cells at doses of 12.5 μmol/L and specific inhibition of MCF-7 breast cancer cells [62]. In a biological assessment, synthetic Dec-NH₂ demonstrated strong broad-spectrum antimicrobial activity, slight mast cell degranulation, and leishmanicidal activity. The peptide displayed low hemolytic function against mouse erythrocytes, EC₅₀ lower 300 µM [61]. A synthetic Dec-NH₂ analog with C-terminal amidation demonstrated much more efficient activity against Gram-positive and Gram-negative bacteria and yeast. When isoleucine was substituted by phenylalanine residue at position 6, the peptide increased its resistance to degradation in bovine fetal serum. Besides that, lower hemolytic activity was obtained for [Pro]⁴-decoralin-NH₂ and [Phe]⁶-Des[Thr]¹¹-decoralin-NH₂. The antimicrobial effect was increased in the case of [Phe]⁹-[Phe]¹⁰-Dec-NH₂ (MIC = 0.39 vs. native peptide of 0.78 µmol/L) against Micrococcus luteus A 270 [63]. Torres et al. synthesized two leucine-substituted Dec-NH₂ analogs; [Leu]⁸-Dec-NH₂, and [Leu]¹⁰-Dec-NH₂ using SPPS. [Leu]¹⁰-Dec-NH₂ analog showed similar activity against E. coli, and P. aeruginosa (MIC 1.6 μmol/L), and higher activities against M. luteus and C. albicans. The same helical structure of the [Leu]⁸-Dec-NH₂ analog exhibited evidential low activities against M. luteus, E. coli, Salmonella arizonae, B. subtilis, P. aeruginosa, and C. albicans [11]. The natural sequence of amidated Dec-NH₂ and eight synthesized analogs, along with their biological activity toward Plasmodium, were reviewed. The Dec-NH₂ template compound did not display antiplasmodial properties; on the other hand, it’s designed analogs showed significant antiplasmodial activity (>95%). The highest antiplasmodial behavior was achieved by mutations made to the N-terminus of Dec [64].

Polybia-MP-I is one of the 14 amino acid residues (Table 1) of mastoparan peptides [65]. The peptide was derived from the venom of the social wasp P. paulista. It causes moderate mast cell degranulation, demonstrates chemotactic action for polymorphonuclear leukocytes, exhibits active antimicrobial activity, and is non-hemolytic to rat erythrocytes [66]. Polybia-MP-I is cytotoxic to leukemic T lymphocytes and strongly selective to these individual cells [67]. Polybia-MP-I has demonstrated antitumor action against bladder and prostate cancer [12]; however, this antitumor activity drastically decreased with the synthesized analogs (replacement of the amino acids at position 7, 8, or 9 with Pro residue). These substitutions influence the original helical structure and electrostatic equilibrium and increase the degree of peptide hydrophilic behavior (Pro⁷ and Pro⁹). Polybia-MP-I exerts pore formation and thus alters the intact cellular structure leading to a cytotoxic and antiproliferative outcome. It can selectively inhibit the proliferation of prostate cancer cell lines (PC-3), human bladder cancer cell lines (Biu87 and EJ), and human umbilical vein endothelial cell lines (HUVEC) at IC₅₀ of 20.8, 25.32, and 36.97 μM, respectively [12].

The peptides polybia-MP-I (IDWKKLLDAAKQIL-NH₂) and Asn-2-polybia-MP-I (INWKKLLDAAKQIL-NH₂) were manually synthesized in the solid phase. Polybia-MP-I and N-2-polybia-MP-I exhibited a significant reduction in the pain threshold at 30, and 50 μg/50 μL as detected at 2, and 8 h after peptide injection into the hind paw of mice [68,69]. The polybia-MP-I analogs (proline replacement) showed reduced antibacterial activity compared to the parent. MIC values of polybia-MP-I were 4, 16, 16, and 32 μM for B. subtilis, E. coli, S. epidermidis, and S. aureus, respectively. The MIC value was 8 µM for C. glabrata versus 16 µM against C. albicans. The fungicidal activity of polybia-MP-I versus both Candida glabrata and C. albicans was measured as an minimum fungicidal concentration (MFC) of 32 μM [70,71].

Polybia-CP has been isolated from P. paulista, and gradually synthesized by SPPS, and its effects on bacteria have been recorded [14]. Polybia-CP’s MICs for E. coli, P. aeruginosa, S. aureus, S. epidemic, and B. subtilis were 16, 128, 4, 16, and 4 μM, respectively, while the MBCs were 8, 16, 128, and 16 μM, for B. subtilis, S. aureus, and E. coli, respectively. The peptide was stable at different temperature ranges of 20–100 °C, and the temperature changes did not affect the MIC values [72]. Polybia-CP showed antimicrobial activities with MIC values of 4–64 μM in eight fungal strains, where the highest activity was noted against C. tropicalis at a MIC of 4 μM [13].

Synthetic Polybia-CP has potent antitumor activity against Biu87 and PC-3 cell lines. Cell proliferation inhibition was observed at IC₅₀ of 17.84 and 11.01 μM, respectively. The cytotoxicity of polybia-CP was explained by the disruption of cell membrane integrity [14].

Polydim-I is a peptide derived from the venom of a neotropical wasp (Polybia dimorpha). The peptide contains 22 amino acid residues and is known for its amphipathic properties due to the presence of hydrophobic amino acid residues (e.g., methionine, leucine, valine, and proline) [15].

Polydim-I was synthesized with high quality (>99%), and the relevant peptide sequence was tested and validated by MS analysis. The synthetic peptide is active against Mycobacterium abscessus subsp. massiliense infections as described in in vitro and in vivo studies. In vitro study, the inhibition was 55 to 68% of M. abscessus subsp massiliense strains growth at a concentration of 15.2 μg/mL in which the cell shape was expressively damaged. The peptide prevents bacterial growth through the inhibition of protein synthesis, did not result in visible morphological changes. Polydim-I treatment at 2 mg/kg/mLW showed significant reduction of the bacterial load in in the lungs, spleen, and liver [15], and the antimicrobial properties against S. aureus, E. coli, Enterococcus faecalis, Acinetobacter calcoaceticus-baumannii were displayed with MIC₅₀ values of 4.1, 50.7, 73.2, and 84.0 μg/mL, respectively [73].

Protonectarina-MP was isolated from Protonectarina syleirae venom and is a member of the 14 amino residue class of mastoparans [74]. The peptide protonectarina-MP-NH₂ (INWKALLDAAKKVL-NH₂) and its analogue protonectarina-MP-OH (INWKALLDAAKKVL-OH) were produced by step-by-step manual SPPS. Protonectarin-MP-NH₂ is a powerful mast cell degranulating peptide with slightly higher degranulating activity (ED₅₀ = 8 ×10⁻⁵ M) than the standard peptide (ED₅₀ = 20 × 10⁻⁵ M). Protonectarina-MP-OH, and even at high concentrations, has reduced degranulation activity. Protonectarina-MP-NH₂ has effective antimicrobial activity against both Gram-positive and Gram-negative bacteria, while protonectarina-MP-OH has much poorer antimicrobial activity [17].

Agelaia-MP is a mastoparan peptide that contains 14 residues (INWLKLGKAIIDAL-NH₂) and is isolated from the venom of the social wasp Agelaia pallipes. It was characterized by its poor antimicrobial action and the lack of chemotaxis toward mast cells [74]. Using the Fmoc strategy, agelaia-MP has been chemically and manually synthesized. At a concentration of 10 μM, the peptide enhances the insulin secretion from the mice pancreatic islets using different glucose doses (2.8, 11.1, and 22.2 mM). In mouse models, agelaia-MP-I has a dose-dependent anti-nociceptive effect. For example, nociception significantly declined when the highest dosage (6.4 nmol) was administered, while the maximal effect was observed 4 h after the peptide injection [16].

Protonectin is derived from the venom of the neotropical social wasp (Agelaia pallipes), with a sequence of ILGTILGLLKGL-NH₂. The peptide exhibits poor hemolysis to rat erythrocytes [74]. Protonectin has some mast cell degranulating activity and potent antimicrobial action with E. coli, P. aeruginosa, B. subtilis, and S. aureus at MICs of 25, 1.7, 3.1, and 12.5 µg/mL, respectively [74].

Protonectin and its three analogues were synthesized through a stepwise solid-phase assay by replacing L-proline. Proline is a unique amino acid among the 20 protein-forming amino acids because its amine nitrogen is linked to two groups of alkyls, making it a secondary amine. The insertion of proline inside the peptide considerably changes the secondary structure. Protonectin has demonstrated potent antibacterial action toward multidrug-resistant S. aureus, and E. coli at MICs of 8, and 32 μM, respectively. MBC values were 8, 8, 16, and 64 µM for B. subtilis, S. epidermidis, S. aureus, and E. coli, respectively, indicating potent bactericidal effect [75].

Philanthotoxin-433 (PhTX-433) is a polyamine-based toxin isolated from Egyptian digger wasp (Philanthus triangulum) venom. The venom induces prey paralysis by suppressing nicotinic acetylcholine receptors (nAChRs) and ionotropic glutamate receptors (iGluRs). PhTX-433 is an important lead compound in neuropharmacology [76,77]. The action of 17 analogs of PhTX-343 against ganglionic (α3β4) and brain (α4β2) nAChRs has been expressed in Xenopus oocytes. IC₅₀ values for PhTX-343 inhibition of α3β4 and α4β2 receptors were 7.7 and 80 nM, respectively [78]. Their total synthesis achieved good yield (77%) and purity (80%) using a mild borane reduction protocol of polyamide precursors to access the polyamine chains. The synthesis of PhTX-433 isomers proved this strategy’s potential for the generation of branched analogs [76].