Designed Multifunctional Peptides for Intracellular Targets

Nature’s way for bioactive peptides is to provide them with several related functions and the ability to cooperate in performing their job. Natural cell-penetrating peptides (CPP), such as penetratins, inspired the design of multifunctional constructs with CPP ability. This review focuses on known and novel peptides that can easily reach intracellular targets with little or no toxicity to mammalian cells. All peptide candidates were evaluated and ranked according to the predictions of low toxicity to mammalian cells and broad-spectrum activity. The final set of the 20 best peptide candidates comprises peptides optimized for cell-penetrating, antimicrobial, anticancer, antiviral, antifungal, and anti-inflammatory activities. Their predicted features are intrinsic disorder and the ability to acquire an amphipathic structure upon contact with membranes or nucleic acids. In conclusion, the review advocates for exploring the wide-spectrum multifunctionality of novel, nontoxic hybrids incorporating cell-penetrating peptides.

Davor Juretić notes in 2025: It is a special pleasure to design, test, and name promising candidates for novel peptide antibiotics. Some of them are also anticancer peptides. Thus, I named adepantins (A1), adepantin-1-analogue (A1A), diPGLa-H (PG2), kiadins, [I2, K19]-ascaphin-8, [K2, K16]-XT-7, trichoplaxin (T1), trichoplaxin-2-analogue (T2A), mapegin (MAPA), ZYK-1 (ZYK), flexampin (FLEX), and temporin-CPP-analogue (TCPP). All peptides are C-terminally amidated. Their primary structures are:

A1 = GIGKHVGKALKGLKGLLKGLGES

A1A = GIKKAVGKALKGLKGLLKALGES

PG2 = KIAKVALKALKIAKVALKAL

T1 = FFGRLKSVWSAVKHGWKAAKSR

T2A = RHHWRRYARIGFRAVRTVIGK

MAPA = KIGKKILKALKGALKELA

ZYK = GIGREIIKKIIKKIGKKIGRII

FLEX = GIKKWVKGVAKGVAKDLAKKIL

TCPP = VKKIVSKIRKLLKGGRRWFRSRRRR