The cyclophilins are widely expressed enzymes that catalyze the interconversion 
of the cis and trans peptide bonds of prolines. The immunosuppressive natural 
products cyclosporine A and sanglifehrin A inhibit the enzymatic activity of the 
cyclophilins. Chemical modification of both the cyclosporine and sanglifehrin 
scaffolds has produced many analogues that inhibit cyclophilins in vitro but 
have reduced immunosuppressive properties. Three nonimmunosuppressive 
cyclophilin inhibitors (alisporivir, SCY-635, and NIM811) have demonstrated 
clinical efficacy for the treatment of hepatitis C infection. Additional 
candidates are in various stages of preclinical development for the treatment of 
hepatitis C or myocardial reperfusion injury. Recent publications suggest that 
cyclophilin inhibitors may have utility for the treatment of diverse viral 
infections, inflammatory indications, and cancer. In this review, we document 
the structure-activity relationships of the nonimmunosuppressive cyclosporins 
and sanglifehrins in clinical and preclinical development. Aspects of the 
pharmacokinetic behavior and chemical biology of these drug candidates are also 
described.