Experimental Drug Development Centre

Purpose: To evaluate the real-world efficacy and usability of PureDelivery® LAN (CatarClear®), a topical proprietary lanosterol (LAN) nano-formulation, for the non-surgical management of naturally occurring cataracts in companion animals. Materials and Methods: About 100 dogs and a smaller cohort of other small animal pets (e.g., cats, rabbits) diagnosed with cataracts of varying stages and etiologies. A clinical data collection study was conducted over twelve months across multiple veterinary practices in Singapore. Over 10 participating veterinary surgeons treated animals with PureDelivery® LAN (CatarClear®), administered topically twice daily for a minimum of six weeks. Efficacy was assessed based on a predefined categorical scale that is significant improvement, slight improvement, no improvement, through ophthalmic examination. Data on ease of administration and overall recommendations were also collected. Findings: Of the treated animals, 98% showed measurable improvement in cataract presentation following the treatment regimen. The improvement was categorized as significant in a notable portion of cases, particularly those with early-stage cataracts. The formulation was reported by veterinarians to be easily administered by pet owners. This study demonstrates that PureDelivery® LAN (CatarClear®) is a highly effective, non-invasive therapeutic option for managing cataracts in companion animals, especially in cases where ophthalmologic surgery is contra-indicated due to age, health risks, anaesthesia concerns, or financial constraints. Unique Contribution to Theory, Practice and Policy: Future studies should be designed as randomized, controlled, and blinded trials. Incorporating objective measures like digital image analysis of lens opacity, electroretinography (ERG), and more detailed visual obstacle course testing would strengthen the findings (20, 21). Longitudinal studies are also warranted to assess the long-term efficacy, safety, and potential for cataract recurrence after cessation of treatment across a wider range of species.

Resulting in several million deaths globally, the COVID-19 pandemic has highlighted the criticality of antiviral drugs during a viral pandemic. Herein, we describe our efforts toward targeting SARS-CoV-2 Mpro, a key viral protease, which led to the discovery of compound 18, a reversible covalent inhibitor with potent antiviral activity against several clinical variants of SARS-CoV-2. Compound 18 demonstrated dose-dependent efficacy in a mouse-adapted SARS-CoV-2 infection model, with favorable pharmacokinetic profiles in mice, rats, dogs, and monkeys.

Zika virus has raised global concerns due to its link to microcephaly and Guillain-Barré syndrome in adults. One of viral nonstructural proteins-NS4B, an integral membrane protein, plays crucial roles in viral replication by interacting with both viral and host proteins, rendering it an attractive drug target for antiviral development. We purified the N-terminal region of ZIKV NS4B (NS4B NTD) and reconstituted it into detergent micelles. Here, we report the assignments of the backbone resonances of NS4B NTD in detergent micelles. The available assignment is useful for understanding its structure and ligand binding to provide useful information for developing NS4B inhibitors.

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor-positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker-toxin with vedotin (MC-VC-PABC-MMAE), yielding the novel peptide drug conjugate D-Cys6-LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non-cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D-Cys6-LHRH vedotin can potentially be used as a treatment for ovarian cancer.

New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target. Recent deep insights into these mycobacterial F1FO-ATP synthase elements opened the door for a renaissance of structure-based target identification and inhibitor design. In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy.

Abstract One of the promises of precision medicine is to understand and act on inter-individual genetic differences in drug responses. SNPdrug3D contains the complete genomic landscape of missense single nucleotide variants (SNV) across the human proteome and at population-wide level that could affect drug binding. In the Singapore SG10K Health and global gnomAD cohorts, comprising variations in over 80,000 individuals, we identified ~ 1.17 million variants mapped to residues near bound drug molecules in protein-drug complexes relative to ~ 6000 drug molecules and experimentally verified effects of selected SNVs, including previously uncharacterized variants, on drug binding in relevant proteins ranging from kinases to cytochrome P450s (CYPs). The latter led to a specific predictor for interpreting variants in the CYP family that vastly outperforms existing tools in the prediction of pharmacogenetic effects. By placing variants and drugs in structural context, SNPdrug3D aids drug development by early flagging of resistance potential through population-specific variability.