The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization (WHO). Since SARS-CoV-2 main protease plays an essential role in the virus’s life cycle, the design of small drug molecules with lower molecular weight has been a promising development targeting its inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate the selected compounds’ binding free energy profiles against SARS-CoV-2 and further unveil the residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding free energy of −49.37 ± 0.15 kcal/mol, followed by compound 7 (−39.83 ± 0.19 kcal/mol), while compound 17 showed the lowest binding free energy (−23.54 ± 0.19 kcal/mol). In addition, the absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug’s ability to bind better at the active site of the SARS-CoV-2 Mpro.

Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (K_iapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log₁₀ reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

This study reported the synthesis and formulation of an adamantane-based collagen mimetic peptide (CMP) hydrogel containing the integrin-binding motif retro-GFOGER, designed to enable the controlled delivery of CMPs with the ability of direct wound healing for the potential treatment of acute wounds. Initially, two adamantane-functionalized CMPs (peptides NL008 and NL010) were synthesized, characterized, and comparatively screened for their in vitro biocompatibility and bioactivity. In vitro evaluations of scratch closure and biocompatibility were assessed on human-derived keratinocytes. Release and permeation of the peptides were evaluated in vitro and ex vivo. Wound closure rates and histological evaluations were performed on male Sprague-Dawley rats over 3, 7, and 14 days for the NL010-HAgel formulation. Peptide NL010 was found to be the most suitable candidate among the adamantane CMPs. For a comparative study, peptide NL010 and its palmitic acid analogue, NL009, were loaded into a hyaluronic acid (HA) hydrogel and lyophilized. The CMP hydrogels exhibited porosity (<30 μm) and were viscoelastic solids. The physicomechanical properties of the formulations showed optimal characteristics for application as wound dressings in terms of textural profile. Peptide NL008 exhibited lower bioactivity and cell viability compared to NL009 and NL010 across various concentrations and cell lines. Peptide release from NL009-HAgel and NL010-HA gel was 74% and 83%, respectively. Across an ex vivo porcine skin membrane, the CMP-HAgel showed good permeation and was retained in the epidermis and superficial dermis. CMP-HAgel at 0.1% (w/v) showed better HaCaT cell viabilities. In vitro assays demonstrated that the NL010-HA gel achieved scratch closure (99.9%) within 24 h, while the NL009-HAgel showed scratch closure (93.7%) within the same time frame. In vivo, NL010-HAgel improved healing by enhancing epithelialization and granulation tissue deposition (via fibroblast and collagen responses). The findings of this study suggested that the CMP cell-instructive hydrogel is a promising platform with the potential to accelerate wound healing.