Several eukaryotic proteins with defined physiological roles may act as precursors of cryptic
bioactive peptides released upon protein cleavage by the host and/or bacterial proteases. Based on this,
the term “cryptome” has been used to define the unique portion of the proteome encompassing proteins
with the ability to generate bioactive peptides (cryptides) and proteins (crypteins) upon proteolytic
cleavage. Hence, the cryptome represents a source of peptides with potential pharmacological interest.
Among eukaryotic precursor proteins, human apolipoproteins play an important role, since promising
bioactive peptides have been identified and characterized from apolipoproteins E, B, and A-I sequences.
Human apolipoproteins derived peptides have been shown to exhibit antibacterial, anti-biofilm, antiviral,
anti-inflammatory, anti-atherogenic, antioxidant, or anticancer activities in in vitro assays and, in some
cases, also in in vivo experiments on animal models. The most interesting Host Defence Peptides
(HDPs) identified thus far in human apolipoproteins are described here with a focus on their biological
activities applicable to biomedicine. Altogether, reported evidence clearly indicates that cryptic peptides
represent promising templates for the generation of new drugs and therapeutics against infectious diseases.