The goal of this research proposal is to target sperm LDH-C4 and disrupt fertilizing ability for male contraception. Our strategy in collaboration with the Matzuk group at Baylor Medical School, will utilize Dec-Tech libraries to screen LDHC for inhibitors that may be used in drug design. In addition using structure based drug design will exploit the recently described inhibitors of LDH-A4. In 2012, a research team from Astra-Zeneca reported a fragment-based approach which resulted in the first drug-like inhibitors of LDHA, fully validated by various methods including ITC and X-ray crystallography. These compounds can be tailored to selectively target testis/sperm cells and reversibly disrupt the function of LDH-C4. Lactate dehydrogenases (designated A and B for somatic forms and C for the sperm isozyme) are highly homologous with 84-89% sequence similarities and 69-75% amino acid identities. The challenge we face is to discover inhibitors with almost 100% selectivity that can be developed as a contraceptive drug. My role in this project is based on my more than 50 years’ experience in research on LDHC. Therefore my qualifications to participate involve this knowledge. I will be responsible for design of experiments to discover selective LDHC inhibitors and interpreting research results from compound screening leading to useful drug design. I will advise research personnel both in individual and group meetings that will be held on a regular basis. I will participate in group meetings with Gates Foundation personnel who monitor progress of this research being conducted at Baylor Medical School in Houston. My input will be required will be required to analyze, interpret and prepare progress reports and publications describing results obtained from these experiments. All of the laboratory work will be done at Baylor College of Medicine in Houston, TX.
|Effective start/end date||11/4/19 → 10/31/22|
- Baylor College of Medicine (7000001109//INV-001902 Yr 1)
- Bill & Melinda Gates Foundation (7000001109//INV-001902 Yr 1)