A novel concept is presented for combinatorial peptide nucleic acid (PNA) synthesis.Novel peptide nucleic acids with improved properties can be anticipated to be generated by this method.Thus, PNAs I can be prepared by Ugi 4-component condensation of amines RNH2, carboxylic acids with nucleobase side chains BCH2CO2H, aldehydes or ketones R1COR2, and isocyanides CNCHXCHYNHPG (PG = protective group), followed by deprotection and repetition of the reaction sequence.