Non-Immunosuppressive Cyclophilin Inhibitors.

Area of Science:

• Biochemistry
• Pharmacology
• Medicinal Chemistry

Background:

• Cyclophilins are enzymes with peptidyl-prolyl cis/trans isomerase activity, crucial in diverse biological functions.
• Cyclophilin A, a key member, acts as the cellular receptor for cyclosporine A (CsA), an immunosuppressive drug.
• Pathophysiological roles, especially in viral infections, drive interest in cyclophilin inhibitors lacking immunosuppressive effects.

Purpose of the Study:

• To review the physiological and pathophysiological roles of cyclophilins.
• To present and discuss various classes of non-immunosuppressive cyclophilin inhibitors.
• To highlight synthetic strategies, structure-activity relationships, and clinical data for these inhibitors.

Main Methods:

• Review of existing literature on cyclophilins and their inhibitors.
• Analysis of chemical modifications of CsA as cyclophilin inhibitors.
• Examination of sanglifehrins and de novo designed compounds as therapeutic leads.
• Discussion of synthetic concepts, biochemical studies, SAR, and clinical trials.

Main Results:

• Identification of three main classes of non-immunosuppressive cyclophilin inhibitors: modified CsA, sanglifehrins, and de novo compounds.
• Demonstration of diverse chemical structures and synthetic approaches for targeting cyclophilins.
• Emphasis on structure-activity relationships and clinical relevance for therapeutic development.

Conclusions:

• Non-immunosuppressive cyclophilin inhibitors represent a promising therapeutic avenue, particularly for viral infections.
• Multiple drug design strategies, from natural product modification to de novo design, are effective.
• Further research into SAR and clinical studies is essential for advancing these compounds.