Review on Plant Protease Inhibitors as Therapeutic Molecules Sangeeta A. Godbole 1 * and Sopan N. Kharat 2 1 Associate Professor, Head Department of Botany, Jai Hind College, Churchgate, Mumbai, Maharashtra, India. 2 Assistant Professor, Head Department of Botany, SSR College of ACS, Silvassa, UT of DNH and DD, India. *Corresponding author e-mail : sangeeta.godbole@jaihindcollege.edu.in Jour Pl Sci Res 38 (1) 277-288 2022 DOI:-https://doi.org/10.32381/JPSR.2022.38.01.30 Plants contain several phytochemical compounds with capacity to exert therapeutic effects on human beings. One such group of molecules are the Protease inhibitors (PIs) which exert inhibitory activity towards several classes of mammalian, bovine, insect or microbial proteinases/proteases. PIs are polypeptides or proteins capable of forming reversible stoichiometric protein–protein complexes with specific proteolytic enzymes. This inhibits the catalytic function of proteolytic enzymes. Study of PIs is important to control proteolysis as it is the key to control the onset of several disease associated phenomena. Although initially, PIs were considered only as protein degrading enzymes, recent studies point them to be signalling molecules in biological activities. In this article, various classes of plant protease inhibitors and their general mode of actions are discussed. The families belonging to the serine protease class of inhibitors (Serpins) are discussed in detail as these constitute an important class of therapeutically important molecules. Data available on the use of PIs for treating a wide range of human diseases and disorders including the still incurable cancers is reviewed. Literature review confirms wide and successful use of Proteasome inhibitors (with similar activities to PIs) in treatment of haematological malignancies. Synthetic proteasome inhibitors are employed to inhibit the proteasome cascades and thus control disease onset and proliferation. Sharing the similar biological activities with the proteasome inhibitors, gives potential for the plant-based PIs to be experimented for similar uses. An attempt is made to report PIs from several plant species and their ongoing clinical trials to study their therapeutic actions. Keywords: Plant, Protease, Inhibitors, Proteinase, Therapeutic, Serine, Serpins. INTRODUCTION Natural PIs are ubiquitous, and many have been isolated and characterised from several plants, animals and microbial species. PIs found in plants are typical polypeptides composed entirely of L – amino acids linked through peptide bonds. They are very stable molecules often resistant to heat, extremes of pH and proteolysis, even by those proteinases that they do not inhibit. This stability is attributed to the high degree of crosslinking through disulphide bridges. Plant inhibitors are often low or devoid of methionine, histidine and tryptophan but are often rich in aspartic acid, glutamic acid, serine and lysine residues. Several glycoproteins PIs are found in animals but no plant PI is found to be in a glycoprotein except the reported case of a papain inhibitor. Thus, plant protease inhibitors are carbohydrate-free peptides or small proteins with molecular weights in the range of 4000 to 80000 Da, although most of them fall between 4000 to 20000 Da. The association of proteases with their inhibitors is strong at neutral pH but decreases in some cases as the pH is lowered from neutrality to 3. Inhibitors capable of simultaneously inhibiting two molecules of enzyme per molecule of inhibitor