To increase access to long-acting contraception, we developed a reversible contraceptive microneedle patch that is simple-to-administer, slowly releases contraceptive hormone (levonorgestrel) for >1 month, and generates no biohazardous sharps waste. After manually pressing the patch to skin for 1 min, microneedles rapidly separate from the patch within the skin due to effervescence triggered by contact with skin’s interstitial fluid, as demonstrated in rats and human participants. Long-acting contraception is achieved by formulating microneedles with a biodegradable polymer [poly(lactic-co-glycolic) acid] that slowly releases levonorgestrel for ~1 month in vitro. In rats, the patch maintained levonorgestrel concentration above the human contraceptive threshold level for >1 month, and a placebo microneedle patch was well-tolerated in human participants. Women of reproductive age in three continents demonstrated interest in and preference for long-acting contraception by microneedle patch. These studies indicate that an effervescent microneedle patch could facilitate greater access to long-acting contraception.

Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RAInterleukin-17 (IL-17) cytokines are homo or heterodimeric proteins formed by combinations of six distinct polypeptides designated IL17A-F 1 . They are essential to a fully functional immune system 2,3 , but dysregulated expression of IL-17A is implicated in autoimmune disorders such as psoriasis, psoriatic arthritis, rheumatoid arthritis and multiple sclerosis 4-6 . The IL-17A covalent homodimer's significance in psoriasis is evidenced by the recent success of anti-IL-17A biologics as therapeutics. Secukinumab (Costentyx TM ), a monoclonal antibody targeting IL-17A, was recently approved for the treatment of moderate to severe plaque psoriasis 7,8 and is being investigated in other IL-17A-driven immunological diseases 9 . Additionally, two other biologics, ixekizumab (anti-IL17A) 10,11 and brodalumab (an antibody to the IL-17 receptor, IL-17RA) 12,13 , have shown efficacy in psoriasis in late stage clinical trials.IL-17A signaling occurs through its membrane-bound receptors, IL-17RA and IL-17RC, and elicits multiple inflammatory and immune responses [14][15][16] . The cytokine binds to IL-17RA with low single-digit nanomolar affinity 14,15,17,18 . and the structure of their complex is known 17 . The emerging biologics block this interaction by binding to one or other of the partners, but our goal was to determine whether it could be blocked or modulated with a small molecule as this could afford orally active agents.Small-molecule inhibition of a protein-protein interaction (PPI) is invariably challenging 19 . Even the discovery of early lead matter tends to be difficult because corporate compound collections are largely designed to target the active centers of enzymes, and are deficient in compounds suitable to the longer and shallower binding sites on which PPIs tend to depend. As the industry expands the "druggable genome", continued efforts at small molecule inhibition of PPIs will be required 20 . ResultsLead small molecule IL-17A antagonists. Our effort to discover small-molecule antagonists of IL-17A was initiated from disclosed inhibitors 21,22 exemplified by compound 1 (Fig. 1), a polyamide with clear structure-activity relationships (SAR) representative of the series. For example, the amide bonds, correct chiral center and cyclopentyl group were all required for activity. Surface plasmon resonance (SPR) measurements showed

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (K = 0.4 ± 0.1 nM) and the highest selectivity (μ/κ = 339, δ/κ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.

The processes and mechanisms of LiNiO2 synthesis during the high-temperature solid state method, using Ni(OH)2 precursor and different lithium salts (Li2CO3 and LiOH), were revealed by the thermal (TG–DTA) and structural (X-ray diffraction (XRD)) analyses. Morphology characterization (scanning electron microscopy (SEM)) and the soluble lithium titration are carried out to support the findings. The results show that the synthetic processes of LiNiO2 generally include raw materials' dehydration, oxidation, and combination; also, the existence of lithium salts makes the oxidation of Ni(OH)2 relatively easier. Comparing the two lithium salts involved in the reactions, LiOH will bring about a transition oxide (Ni8O10) and lower the initial reaction temperature for LiNiO2 generation. In addition, a decent temperature under 800 °C, a preheat treatment in 500–600 °C, and a properly longer heating time are suggested to be significant for obtaining the ideal LiNiO2 materials.

As of today, there is not any direct report yet of the degree to which missing residues exist for experimentally determined membrane protein (MP) structures, which constitute more than half of current drug targets. With a chain- and position-specific visualisation and a statistical analysis of all MP structures inside PDB (as of September 25, 2019), this article argues that the experimentally uncharted territories (EUTs, i.e., consisting of missing residues) within PDB are pluggable and should be plugged with an experimental data-driven hybrid approach, and calls for continued development of MP structural determination with less and less EUTs, in light of MPs' crucial role in biological and biomedical research, both fundamental and pharmaceutical.

The importance of antibodies in health care and the biotechnology research and development demands not only knowledge of their experimental structures at high resolution, but also practical implementation of this knowledge for both effective and efficient design and production of antibody for its use in both medical and research applications. While the experimental wet-lab approach is usually costly, laborious and time-consuming, computational (dry-lab) approaches, in spite of their intrinsic limitations in comparison with its experimental (wet-lab) counterpart, provide a cheaper and faster alternative option. For the first time, this article reports a comprehensive set of structural electrostatic features extracted from experimentally determined antigen-antibody-related structures, including especially those structural electrostatic features at the interfaces of all experimentally determined antigen-antibody complex structures as of February 29, 2020, to facilitate effective and efficient machine learning-based computational antibody design using currently available experimental structures inside Protein Data Bank.

To date, Cartesian (x, y, z) coordinate system (CCS) has been the default approach to geometrically specify atomic spatial positions in protein structures since the launch of Protein Data Bank (PDB) in 1971. To this end, this paper proposes a local spherical coordinate system (SCS) approach as an alternative to the default approach and a previously reported global SCS approach. The local SCS approach here requires only two parameters (θ and φ), instead of x, y and z as required by the default CCS approach. Essentially, CCS and SCS are like the two sides of one coin, i.e., geometric coordinate system for three-dimensional position specification. Therefore, this paper furthermore argues that it is time to flip the coin over, and have a look at the other side of the coin, e.g., the local SCS approach, which possesses an intrinsically lower degree of descriptional complexity than that of the default CCS approach, and constitutes a potentially useful alternative perspective for all protein structural research field.

For voltage-gated Ca2+ channel (VGCC), its α2δ subunits are traditionally considered to be auxiliary subunits that regulates VGCC trafficking to the plasma membrane. The antiepileptic, antinociceptive and anxiolytic gabapentin (GBP) has previously been shown to bind the VGCC α2δ subunits with high affinity to disrupt VGCC trafficking. Yet, the interaction between GBP and α2δ still remains poorly understood from a structural point of view. For instance, it is not clear yet what the structural implication is of α2δ-1-bound GBP against VGCC trafficking. With a set of experimental data-driven structural analysis of the VGCC α2δ-1 and its ligand GBP, this article postulates for the first time that: 1), α2δ-1 bound GBP stabilizes the α2δ-1-GBP complex structure; 2), α2δ-1 bound GBP restrains the conformational flexibility of α2δ-1; 3), α2δ-1-bound GBP establishes an electrostatic axis consisting of Q535 (Gln535)-R241 (Arg241)-GBP (gabapentin)-D452 (Asp452), which constitutes an energetically favourable contribution towards the structural stability of the α2δ-1-GBP complex and helps restrains the conformational flexibility and local structural rigidification of α2δ-1; and 4), GBP-induced local conformational inflexibility and structural rigidification of α2δ-1 is one key step in the pharmacological disruption of VGCC trafficking by GBP.