Offers a review of the most current methodologies of constructing constrained helices. PART I OVERVIEWS 1.1 Protein-protein interactions 1.1.1 Function 1.1.2 Structural basis and features 1.1.3 Targeting PPIs by small molecules 1.2 Peptides as molecular tools 1.2.1 Advantages 1.2.2 Disadvantages 1.3 Helical structures 1.3.1 Classification 1.3.2 Function 1.3.3 Characterization 1.4 Stabilization of helices via cyclization 1.4.1 Classification 1.4.2 Overview PART II CONSTRUCTION OF CONSTRAINED HELICES 2.1 Side-chain crosslinking (History, chemistry, features and limitations) 2.1.1 Disulfide bond I+3, i+7, conotoxin 2.1.2 Amide or ester 2.1.3 All-hydrocarbon I+4/3/7, stitched peptide, de alpha methylation, reduced, Moore 2.1.4 Thiol ether I+3, Woolley, Heinis, Lin, DeGrado, Pentelute, Smith, Chou, Dawson, Li 2.1.5 Azole Chorev, Spring, Arora 2.2 End nucleation 2.2.1 Hydrazone 2.2.2 All-hydrocarbon Arora, Alewood 2.2.3 Disulfide bond 2.2.4 Thiol ether 2.2.5 Amide PART III EFFECTS OF CYCLIZATION ON HELICES 3.1 Helicity 3.1.1 Ring size 3.1.2 Rigidity (alpha methylation, double bond, Z/E) 3.1.3 Substitution (chirality, group size) 3.1.4 Comparison 3.2 Binding affinity 3.2.1 Helicity 3.2.2 Cyclization position 3.2.3 Substitution 3.3 Cell permeability 3.3.1 Helicity 3.3.2 Hydrophobicity 3.3.3 Isoelectric point 3.4 Nonspecific toxicity 3.3.1 Helicity 3.3.2 Hydrophobicity 3.3.3 Isoelectric point PART IV APPLICATIONS OF CONSTRAINED HELICES (physiology and pathology of the target, small molecules/antibodies, structural basis, peptide modulators) 4.1 Cancer ER, BCL-2, MDM2/X, HIF, NOTCH, RAS, beta-catenin, IRS1, Rab, EGFR, KRAS 4.2 Infectious Disease HIV, bacteria, RSV 4.3 Nervous system disease NMDA, Galanin, Neuropeptide Y 4.4 Respiratory system disease Interleukin 13 PART V OUTLOOK 5.1 Methodology development 5.2 Applications