THPdb (http://crdd.osdd.net/raghava/thpdb/) is a manually curated repository of Food and Drug Administration (FDA) approved therapeutic peptides and proteins. The information in THPdb has been compiled from 985 research publications, 70 patents and other resources like DrugBank. The current version of the database holds a total of 852 entries, providing comprehensive information on 239 US-FDA approved therapeutic peptides and proteins and their 380 drug variants. The information on each peptide and protein includes their sequences, chemical properties, composition, disease area, mode of activity, physical appearance, category or pharmacological class, pharmacodynamics, route of administration, toxicity, target of activity, etc. In addition, we have annotated the structure of most of the protein and peptides. A number of user-friendly tools have been integrated to facilitate easy browsing and data analysis. To assist scientific community, a web interface and mobile App have also been developed.

Skin, being the largest organ of the body, is an important site for drug administration. However, most of the drugs have poor permeability and thus drug delivery through the skin is very challenging. In this study, we examined the transdermal delivery capability of IMT-P8, a novel cell-penetrating peptide. We generated IMT-P8-GFP and IMT-P8-KLA fusion constructs and evaluated their internalization into mouse skin after topical application. Our results demonstrate that IMT-P8 is capable of transporting green fluorescent protein (GFP) and proapoptotic peptide, KLA into the skin and also in different cell lines. Interestingly, uptake of IMT-P8-GFP was considerably higher than TAT-GFP in HeLa cells. After internalization, IMT-P8-KLA got localized to the mitochondria and caused significant cell death in HeLa cells signifying an intact biological activity. Further in vivo skin penetration experiments revealed that after topical application, IMT-P8 penetrated the stratum corneum, entered into the viable epidermis and accumulated inside the hair follicles. In addition, both IMT-P8-KLA and IMT-P8-GFP internalized into the hair follicles and dermal tissue of the skin following topical application. These results suggested that IMT-P8 could be a potential candidate to be used as a topical delivery vehicle for various cosmetic and skin disease applications.

Cadherin-23, a giant atypical cadherin, form homophilic interactions at the cell-cell junction of epithelial cells and heterophilic interactions with protocadherin-15 at the tip links of neuroepithelial cells. While the molecular structure of the heterodimer is solved, the homodimer structure is yet to be resolved. The homodimers play an essential role in cell-cell adhesion as the downregulation of cadherin-23 in cancers loosen the intercellular junction resulting in faster migration of cancer cells and a significant drop in patient survival. In vitro studies have measured a stronger aggregation propensity of cadherin-23 compared to typical E-cadherin. Here, we deciphered the unique trans-homodimer structure of cadherin-23 in solution and show that it consists of two electrostatic-based interfaces extended up to two terminal domains. The interface is robust, with a low off-rate of~8 9 10 À4 s À1 that supports its strong aggregation propensity. We identified a point mutation, E78K, that disrupts this binding. Interestingly, a mutation at the interface was reported in skin cancer. Overall, the structural basis of the strong cadherin-23 adhesion may have far-reaching applications in the fields of mechanobiology and cancer.

No abstract

Adherin-junctions are traditionally described by the homophilic-interactions of classical cadherin-proteins at the extracellular region. However, the role of long-chain non-classical cadherins like cadherin-23(Cdh23) is not explored as yet even though it is implicated in tissuemorphogenesis, cancer, and force-sensing in neuronal tissues. Here, we identified a novel antiparallel-binding interface of Cdh23 homodimer in solution by combining biophysical and computational methods, in-vitro cell-binding, and mutational modifications. The dimer consists of two electrostatic-based interfaces extended up to two terminal domains, atypical to classical-cadherins known so far, and forms the strongest interactions in cadherin-family as measured using single-molecule force-spectroscopy. We further identified single pointmutation, E78K, that completely disrupts this binding. Interestingly, the mutation, S77L, found in skin cancers falls within the binding interface of the antiparallel-dimer. Overall, we provide the molecular architecture of Cdh23 at the cell-cell junctions which are likely to have farreaching applications in the fields of mechanobiology and cancer.

Although unglycosylated HuEpo is fully functional, it has very short serum half-life. However, the mechanism of in vivo clearance of human Epo (HuEpo) remains largely unknown. In this study, the relative importance of protease-sensitive sites of recombinant HuEpo (rHuEpo) has been investigated by analysis of structural data coupled with in vivo half-life measurements. Our results identify α3-α4 inter-helical loop region as a target site of lysosomal protease Cathepsin L. Consistent with previously-reported lysosomal degradation of HuEpo, these results for the first time identify cleavage sites of rHuEpo by specific lysosomal proteases. Furthermore, in agreement with the lowered exposure of the peptide backbone around the cleavage site, remarkably substitutions of residues with bulkier amino acids result in significantly improved in vivo stability. Together, these results have implications for the mechanism of in vivo clearance of the protein in humans.